摘要:

14 Alkaloids” By H. F. HODSON The Wellcome Research 1aboratories Beckenham Kent BR3 3BS VOLUMEXII’ of ‘The Alkaloids’ covering the literature to about mid-1968 provides reviews of diterpene alkaloids and the alkaloids of Afstonia,Senecio and the Papaveraceae; there is also a further summary of new alkaloids unclassified or of unknown structure and a chapter on the forensic chemistry of alkaloids. A new one-volume survey2 has expert contributions on the most important classes of alkaloids and includes chapters on biosynthesis and on plant syste- matics. Another new publication3 consists of a comprehensive (to mid-1968) set of tables listing the families and genera of alkaloid-bearing plants and the gross structures empirical formulae and physical constants of the alkaloids therein.A review4 of naturally occurring quinazoline derivatives also includes condensed systems such as the quinazolinocarbolines. The chemical ionisation (C.I.) mass spectra of alkaloids from nine major groups have been studied5 and the resulting structural information has been compared with that obtained by conventional electron impact mass spectrometry. An account6 of the applica- tion of enamines to the synthesis of natural products has extensive coverage of alkaloid synthesis. 1 Pyrrolizidine Alkaloids N.m.r. studies’ have shown that madurensine has structure (I ; R = H) with the macro-ring attached through C(6) and not C(7) as previously supposed ;it is the first example of this type. Ring A exists wholly in the endo-buckled conforma- tion and the macro-ring is completely strain-free.7-Acetylmadurensine (1 ; R = Ac) and the isomer [l R = Ac C(7) and C(6) substituents interchanged] co-occur with madurensine. Loroquin8 (2),a new necine from the highly toxic ’ R. H. F. Manske ‘The Alkaloids’ Academic Press New York 1970 vol. 12. S. W. Pelletier ‘Chemistry of the Alkaloids’ Van Nostrand Reinhold New York 1970. R. F. Raffauf ‘A Handbook of Alkaloids and Alkaloid-containing Plants’ John Wiley and Sons Inc. New York 1970. S. Johne and D. Groger Die Pharmazie 1970 25 22. H. M. Fales H. A. Lloyd and G. W. A. Milne J. Amer. Chem. SOC.,1970 92 1590. M. E. Kuehne Synthesis 1970 510. ’ C. C. J. Culvenor L. W. Smith and R. I. Willing Chem. Comm. 1970 65. J. Borges del Castillo A.G. Espana de Aguirre J. L. Breton A. G. Gonzalez and J. Trujillo Tetrahedron Letters 1970 12 19. * The literature up to June 1970 on this topic has been reviewed in a Chemical Society Specialist Periodical Report entitled ‘The Alkaloids’. 468 H. F. Hodson H OH CH2*OH (1) Urechites karwinsky (Apocynaceae) has the hydroxymethyldihydropyrrolizine structure characteristic’ of the metabolites (in animals) of the hepatotoxic pyrrolizidine alkaloids. The preparation and properties of these hydroxy- methylpyrrole types such as dehydroheliotridine (3) have been further studied.’ 2 Pyridine Alkaloids N-Methylpiperidine N-oxide and an N-methylpyridinium salt have been isolated from the orchid Vandopsis longicaulis.’ The ‘unnatural’ alkaloid 3’-methylnicotine (4) has been obtained from Nicotiana glutinosa after feeding with labelled 1,3-dimethyl- 1-pyrrolinium chloride a homologue of a natural precursor of the pyrrolidine ring of nicotine.12 This is the first report of such an incorporation of an ‘unnatural’ precursor and demonstrates that for this particular step in nicotine biosynthesis the enzyme system is not completely specific.A tertiary base valerianine from Valerianu oficinalis has been recog- nised13 as the methyl ether (5)of tecostidine; a neat synthesis13 of (5)commenced (4) (61 (5) with a diene condensation to give the dihydropyranyl ether (6). The quaternary metho-salts of the isomeric skytanthines have proved to be useful substrates for investigating the influence of stereochemical effects on the course of the Hofmann elimination.l4 Two syntheses of the fungal alkaloid nigrifactin’ 5Q have been reported.’ 5b J. A. Joule Ann. Reports (B) 1969 66 470; A. R. Mattocks Nature 1970 228 174. lo C. C. J. Culvenor J. A. Edgar L. W. Smith and H. J. Tweeddale Austral. J. Chem. 1970 23 1853 1869. S. Brandange and B. Liining Acta Chem. Scand. 1970 24 353. It M. L. Rueppel and H. Rapoport J. Amer. Chem. SOC.,1970,92 5528. l3 B. Franck U. Peterson and F. Huper Angew. Chem. Internat. Edn. 1970 9 891. l4 E. J. Eisenbraun H. Auda K. S. Schorno G. R. Waller and H. €3. Appel J. Org. Chem. I970,35 1364. (a)J. A. Joule Ann. Reports (B),1969,66,471;(b)M. Pailer and E. Haslinger Monatsh. 1970 101 508; H. W. Gschwend Tetrahedron Letters 1970 2711.Alkaloids 469 3 Lupin Alkaloids Independent syntheses of ( )-lamprolobine'6" illustrate three fundamentally different approaches to a relatively simple system.'6b The synthetic ketolactam (7) the stereochemistry of which was incorrectly assigned in the earlier com- munication has been converted to the Czo Orrnosia alkaloids ormosanine (+)-piptanthine and (+)-panamhe in the first synthesis of alkaloids of this type.l7 Leontiformine from Leontice feontopetafum has the piperidylquinolizidine structure (8),'* the enantiomer of which was previously obtained by degradation of sparteine. 09 IH H CHO H HH 6(7) OMe R (9) 4 Quinoline Alkaloids The angular pyranoquinolines (1 1 ;R = H and MeO) are produced in high yield by treating the epoxides (9; R = H and MeO) with base." This reaction which l6 (a)J.A. Joule Ann. Reports (B) 1968 65 491 ;(b) S. I. Goldberg and A. H. Lipkin J. Org. Chem. 1970,35 242; E. Wenkert and A. R. Jeffcoat ibid. p. 515; Y. Yamada K. Hatano and M. Matsui Agric. and Bid. Chem. (Japan) 1970 34 1536. I ' H. J. Liu Z. Valenta and T. T. J. Yu Chem. Comm. 1970 11 16. N. M. Mollov and I. C. Ivanov Tetrahedron 1970 26 3805. l9 R. M. Bowman M. F. Grundon and K. J. James Chem. Comm. 1970,666. 470 H. F. Hodson provides a new synthesis of flindersine proceeds via the allylic alcohol and the quinone methide (10); formation of the 2-quinolone methide would involve disruption of the benzenoid system and it is probably for this reason that linear pyranoquinolines are not formed.Atalaphylline (12) and N-methylatalaphylline two alkaloids from Atalantia monophylla are the first acyclic C-isoprenoid acridones” (ctacronycine). An impressive stereoselective total synthesis2’ of quinine begins’ la with an elegant four-step synthesis (Scheme 1) of ( f)-N-benzoylmeroquinene [16 ; 0 + HQ iii iv i ii H& Q CO-Ph N CO*Ph CO-Ph (13) (14) (15) Reagents i NaN,-PPA; ii H,-Rh/AI,O,; iii N,O,; iv heat; Scheme 1 i pHv + R~ ” OH R vii --* HO R R=MeoQfJ v Bui,AIH ;vi PhH-AcOH ; vii 02-Bu‘O-BuLOH-Me2S0 Scheme 2 2o T. R. Govindachari N. Viswanathan B. R. Pai V. N. Ramachandran and P. S. Subramaniam Tetrahedron 1970 26 2905. ’ (a)M. UskokoviC J.Gutzwiller and T. Henderson J. Amer. Chem. SOC.,1970,92,203 ; (b)J. Gutzwiller and M. UskokoviC ibid.. 1970. 92 204. A lkaloids 471 natural 3(R),4(S)-enantiomer depicted] from (1 3). A Schmidt reaction followed by hydrogenation gave the cis-lactam (14) which was converted to the N-nitro- solactam ; thermal rearrangement then produced the diazolactam (1 5) which fragmented with loss of nitrogen to give (&)-(16). The quinoline portion of the molecule was then introduced2 Ib by the reaction between 6-methoxylepidyl- lithium and the methyl ester of (&)-(l6) to give the ketone (17). Reduction to the alcohol mixture (18) was followed by resolution to give the desired 3(R),4(S)-material still as a mixture of C-8 epimers cyclisation to a mixture (19) of deoxy- quinine and deoxyquinidine and finally base-catalysed oxygenation to a readily separable mixture of the erythro-isomers quinine (20) and quinidine (21) together with only very small amounts of the threo-compounds epiquinine and epi- quinidine.Such a high stereoselectivity was also observed in a very similar hydroxylation step utilised in synthesis of ( f)-6-methoxyrubane and a partial synthesis of quinine and quinidine.22 5 Isoquinoline Alkaloids An interesting hypothesisz3 connects the behavioural and pharmacological effects of alcohol ingestion with the in uiuo production of isoquinoline alkaloids. Tetrahydropapaverinol (THP) is a minor but normal metabolite of 3,4-dihydroxyphenylethylamine (dopamine) in animals arising by combination of dopamine with its metabolite 3,4-dihydroxyphenylacetaldehyde.In uitro experi-ment~~~',~ have now shown that in animal tissues the presence of ethanol or its metabolite acetaldehyde greatly enhances the formation of THP by interfering with the normally rapid metabolic removal of 3,4-dihydroxyphenylacetaldehyde; this effect is particularly marked in brain tissue.Alkaloids of the salsolinol type may also be formed by direct reaction of acetaldehyde with d~pamine~~' or other biogenic arnine~.~~ that Even more intriguing is the s~ggestion~~" THP metabolism in man could parallel that of the opium poppy thus providing a biochemical explanation of the observed similarities between alcohol addiction and narcotic addiction. Gigantine (22)is not a 4-hydroxytetrahydroisoquinolineas originally supposed but is2' an example of the rare 5,6,7-trioxygenated tetrahydroisoquinoline cactus OH Meomme Me0 \ Me (22) 22 M.Gates B. Sugavanam and W. L. Schreiber J. Amer. Chem. SOC. 1970 92 205. 23 (a)V. E. Davis and M. J. Walsh Science 1970,167,1005; (b)V. E. Cavis M. J. Walsh and Y. Yamanaka J. Pharmacol. Exp. Therapy 1970 174 401; (c) Y. Yamanaka M. J. Walsh and V. E. Davis Nature 1970,227 1143. 24 G. Cohen and M. Collins Science 1970 167 1749. 25 G. J. Kapadia M. B. E. Fayez M. L. Sethi and G. Subba Rao Chem. Comm. 1970 856. 472 H. F. Hodson alkaloids; it has been synthesised.26 A new route to the benzylisoquinoline petaline includes a Stevens re-arrangement.27 The mass spectra of tetrahydroprotoberberine methines” and the U.V.spectra of the bis-methine~~~ can be useful for locating substituents in the parent alka- loids; the c.d. spectra of this group have also been studied.30 The absolute stereochemistry at C(10) of (+)-chelidonine has been established by the method of partial resolution during esterification with racemic a-phenylbutyric anhy- dride ;(+ )-chelidonine is thus shown to have the lqR) 11(S) 12(R)-configuration (23).30 Although the structure of lanuginosine (24) has now been confirmed by ~ynthesis,~ a new apparently different oxoaporphine oxoxylopine from Stephania abyssinica has been assigned the same structure mainly on spectro- scopic evidence.32 OMe (24) The Pschorr cyclisation continues to find application in the synthesis of morphinandienones and ap~rphine~~ alkaloids.A variation employs photolytic instead of thermal decomposition of the diazonium salt and in some cases this photo-Pschorr reaction may have advantages over the conventional procedure. Moreover the homomorphinandienone (f)-0-methylandrocymbine was pre- pared by irradiation of the diazonium salt (25) whereas thermal decomposition produced only the related l,l-spiroisoquinoline.35In a new approach the phenolic (2-bromobenzyl)isoquinoline (26) gave the corresponding aporphine domesticine in about 30 % yield under benzyne-forming condition^.^^ However 26 G. J. Kapadia G. S. Rao M. B. E. Fayez B. K. Chowdhury and M. L. Sethi Chem. and Ind. 1970 1593. 21 G. Grethe H.L. Lee M. R. UskokoviC and A. Brossi Hefu. Chim. Acta 1970,53 874. 28 L. DolejS and J. Slavik Org. Mass Spectrometry 1970,3 141. 29 V. Simanek V. Preininger P. Sedmara and F. Santavy Coll. Czech. Chem. Comm. 1970,35 1440. 30 G. Snatzke J. Hrbek L. Hruban A. Horeau and F. Santavy Tetrahedron 1970 26 5013. 31 T. R. Govindachari N. Viswanathan S. Narayanaswami and B. R. Pai Indian J. Chem. 1970,8,475. 32 S. M. Kupchan M. I. Suffness and E. M. Gordon J. Org. Chem. 1970 35 1682. 33 E.g. M. P. Cava and M. Lakshmikantham J. Org. Chern. 1970 35 1867; M. P. Cava and M. Srinivasan Tigtrahedron 1970 26 4649. 34 T. Kametani K. Fukumoto and K. Shishido Chem. and Ind. 1970 1566. 35 T. Kametani M. Koizumi and K. Fukumoto Chem. Comm. 1970 1157. 36 S. V.Kessar S. Batra and S. S. Gandhi Indian J. Chem. 1970 8. 468. Alkaloids 473 under the same conditions the (3-bromobenzyl) compound (27) yielded no aporphine or any other product resulting from internal capture of an ar~ne.~~ 0 OMe \-Lw (26) (27) For many years (+)-tubocurarine chloride has been accepted as a bis-quatern- ary alkaloid and has often been quoted as an example of a typical curarising agent with two quaternary centres some 14A apart. A re-in~estigation,~' prompted by apparent anomalies in the dequaternisation and requaternisation of ( +)-tubocurarine chloride has now shown that it has the monoquaternary structure (28); the quaternary-tertiary nature was immediately apparent from spectroscopic observations and the sites of the quaternary and tertiary functions were established by cleavage with sodium and liquid ammonia.With one exception new bis-isoquinoline alkaloids isolated during the year are minor variants of well established structural types. The exception is can- centrine (29)39from Dicentra canadensis; this completely novel structure based on morphine and cularine units is surprising in a group where binary alkaloid structures are dominated by ether-linked benzylisoquinolines and aporphines. Hofmann degradation of cancentrine followed by 0-methylation and reduction N- (29) R = H (30)-R = Me 37 M. S. Gibson G. W. Prenton and J. M. Walthew J. Chem. SOC.(C),1970 2234. 38 A. J. Everett L. A. Lowe and S. Wilkinson Chem. Comm. 1970 1020. 39 G. R. Clark R. H. F.Manske G. J. Palenik R. Rodrigo D. B. MacLean L. Baczyn- skyj D. E. F. Gracey and J. K. Saunders J. Amer. Chem. Sac. 1970,92,4998. 474 H. F. Hodson gave an 0-methyldihydromethine (30) the structure of which was established by X-ray crystallography. Structure (29) for cancentrine then followed from n.m.r. studies on the alkaloid itself.39 Two hasubanan alkaloids stephavanine (31) from Stephania abyssinica and stephisoferuline (32) from S. hernandifolia both have novel ketal and ester functions. The structure and absolute configuration of (3 1)40a was established by X-ray analysis and those of (32)40b by chemical and spectroscopic correlation with 4-demethylhasubanonine. An extension of previous work on the synthesis of the hasubanan skeleton has culminated in a synthesis4' of (+)-hasubanmine itself.HO CH:CH*CO-O 'OMe OH OMe The mass spectral fragmentations of several Erythrina alkaloids have been examined and and the information has been used together with other spectroscopic evidence to establish the structure (33; R' = R2 = Me)43 for erythristemine from E. lysisternurn. The configuration of the 1 1 -methoxy-group and final confirmation of structure were provided by X-ray ~rystallography.~~ Erythristemine is the first reported ring c-oxygenated aromatic erythrina alkaloid; a second from E. indica is er~thrinine~~ (33; R'R' = -CH 2 -9 R2 = H,configuration of OH not specified). Phelline cornosa has yielded seven homoerythrinane alkaloids including the novel epoxides (34; R' = R2 = MeO) and (34; R'R2 = OCH,0).45 The first homoerythroidine types almost certainly (35; R = H and R = Me) have been isolated from P.billi~rdieri.~~ A synthesis of (+)-rhoeagenine diol constitutes the first formal total synthesis of rh~eadine.~' " (a)S. M. Kupchan M. I. Suffness R. J. McClure and G. A. Sim J. Amer. Chem. Soc. 1970,92,5756; (b)S. M. Kupchan and M. I. Suffness Tetrahedron Letters 1970,4975. 41 T. Ibuka K. Tanaka and Y. Inubushi Tetrahedron Letters 1970,481I. 42 R. B. Boar and D. A. Widdowson J. Chem. SOC.(B) 1970 1591. 43 D. H. R. Barton P. N. Jenkins R. Letcher D. A. Widdowson E. Hough and D. Rogers Chem. Comm. 1970 391. 44 K. Ito H. Furukawa and H. Tanaka Chem. Comm. 1970 1076. 45 N. Langlois B. C. Das P. Potier and L.Lacombe Bull. Soc. chim. France 1970 3535. '' H. N. Mai N. Langlois B. C. Das and P. Potier Compt. rend. 1970 270C 2154. 47 H. Irie S. Tani. and H. Yamane Chem. Comm. 1970 1713. Alkaloids 475 Cryptopleurospermine (36)48 from Cryptocarya pleurosperw is a base of unique type ;a biosynthesis involving C-N cleavage and oxidation of a benzyliso- quinoline appears likely. co OMe (36) 6 Amaryllidaceae Alkaloids X-Ray analysis of 6-hydroxybuphanamidine and haemanthamine has confirmed the previous assignments of absolute configurations in the crinane tazettine and montanamine series.49 Apparent anomalies in the chemistry and mass spectra of narcissidine which were not completely explained by an earlier reformulation have finally been settled by X-ray crystallography which establishes structure (37) a revision of the related alkaloids parkicine and ungiminorine is also necessary.Synthetic (37) S. R. Johns J. A. Lamberton A. A. Sioumis and R. I. Willing Austral. J. Chem. 1970 23 353. '* J. C. Clardy F. M. Hauser D. Dahrn R. A. Jacobson and W. C. Wildrnan J. Amer. Chem. SOC.,1970,92,6337. J. c.Clardy W. C. Wildman and F. M. Hauser J. Amer. Chem. SOC.,1970,92 1781. 476 H. F. Hodson and spectroscopic studies51 have also led to a revision of the structures of narciclasine (38) and the derived narciprimine (39). OH (38) (39) A synthesis of (f)-dihydrolycorine (41) hinged on the formation of (40; R = OH) by a Schmidt reaction on the appropriate tetrahydrofluorenone carbinol; conversion to the carboxylic acid (40;R = C02H) then provided a key intermediate with the full lycorine carbon skeleton and a double bond correctly sited for the stereospecific introduction of the ring-c hydroxy-gr~ups.~~ A new route53 to the crinane skeleton commenced with the stereospecific n N.CH2* Ph 51 (a)A.Mondon and K. Krohn Chem. Ber. 1970 103 2729; (6) Tetrahedron Letters 1970 2123; (c) G. Savona F. Piozzi and M. L. Marino Chem. Comm. 1970 1006. 52 H. Irie Y. Nishitani M. Sugita and S. Uyeo Chem. Comm. 1970 1313. 53 I. Ninomiya T. Naito and T. Kiguchi Chem. Comm. 1970 1669. Alkaloids 477 photocyclisation of the N-benzoylenamine (42) to give (43) and thence by the steps indicated to (+)-crinane (44). Among other syntheses of crinane types one a phenol-coupling route to (+)-maritidine is of interest for the use of vanadium oxytrichloride in the oxidation step to the intermediate dienone (45) (45).54 A notable achievement is the stereospecific synthed5 of (_+)-haemanthi- dine (47) and thence (+)-tazettine from the lactam acid (46) by an extension of a previously established55b route from (46) to a simpler crinene system; the essential feature was the interpolation of a series of steps which ensured the desired functionality in ring c.Cherylline (48) isolated from several Crinurn spp. has the structure and absolute configuration shown ;56 it has been synthesised as the racemateS7" and as the natural S-enanti~mer.~~' OH 7 Mesembrine Alkaloids N.m.r.studies indicate that mesembranol and epimesembranol exist in the unexpected conformation (50; R' = OH R2 = H and R' = H R2 = OH) in which the aryl group occupies a quasi-axial position and 0.r.d. studies based on this conformation required the revision of the absolute configuration of the mesembrine alkaloids;58 i.e. mesembranol should be (49; R = Me). This has now been confirmed by X-ray analysis of 6-epimesembranol methi~dide.~ '' M. A. Schwarz and R. A. Holton J. Amer. Chem. SOC.,1970,92 1090. 55 (a)J. B. Hendrickson T. L. Bogard and M. E. Fisch J. Amer. Chem. SOC.,1970 92 5538; (6)J. D. Hobson Ann. Reports 1965 62 381. 56 A. Brossi G. Grethe S. Teitel W. C. Wildman and D. T. Bailey J. Org. Chem. 1970,35 1100. '' (a)A. Brossi and S. Teitel Tetrahedron Letters 1970,417; (b)J.Org. Chem. 1970,35 3559. 58 P. W. Jeffs R. L. Hawks and D. S. Farrier J. Amer. Chem. SOC.,1969,91 3831. 59 P. Coggon D. S. Farrier P. W. Jeffs and A. T. McPhail J. Chem. SOC.(B) 1970 1267. 478 H. F. Hodson Among four new mesembrine alkaloids from Sceletiurn stricturn are two phenolic bases (49;R = H) and the corresponding 4,5-dehydro-deri~ative.~* OH Ar ($+R1 NMe H OH (49) (51) S. jouberti is the first Sceletiurn sp. reported not to contain alkaloids with the full mesembrine skeleton. Instead it has yielded three novel bases with a bio- genetically interesting seco-mesembrine skeleton they are joubertiamine (5l) dihydrojoubertiamine and the dienone dehydrojoubertiamine.6 8 Indole Alkaloids Simple P-carbolines isolated for the first time include 4-methoxy- 1-vinyl-P-' carboline62 from Picrasrna javanica perlolyrine (52)63from Lolium perenne shepherdine (53; R' = H R2 = Me)64 from Shepherdia canadensis the base (53; R' = Me R2 = H)65 from Phalaris arundinacea and the pyridylcarboline -R1o~T-J'JNR~\ R' R2 Y (52) CH20H (53) -(54) 6o P.W. Jeffs G. Ahmann H. F. Campbell D. S. Farrier G. Ganguli and R. L. Hawks J. Org. Chem. 1970,35 3512. 61 R. R. Arndt and P. E. J. Kruger Tetrahedron Letters 1970 3237. 62 S. R. Johns J. A. Lamberton and A. A. Sioumis Austral. J. Chem. 1970 23 629. 63 J. A. D. Jeffreys J. Chem. SOC.(0,1970 1091. 64 W. A. Ayer and L. M. Browne Canad. J. Chem. 1970,48 1980. " R. C. S. Audette H. M. Vijayanagar J.Bolan and K. W. Clark Canad. J. Chem. 1970,48 149. A lkaloids 479 (54)66from Nauclea diderrichii; the biogenetic interest of(54) is heightened by the co-occurrence of several other simple P-carbolines and some 5-substituted derivatives of methyl nicotinate. Studies on the terpenoid carbazole~~~~ from Murraya koenigii have continued and during the year no fewer than eight new alkaloids have been isolated by various gro~ps.~~~~ All are variations on the now well-established theme and include the pentacyclic murrayazolidine (55)67d and mahanirnbi~ine~'" = iso-( rnahanimbi~~e)~~' (56; R' = Me R2 = H) which has the 6-methylcarbazole structure originally assigned to mahanimbine (56; R' = H R2 = Me). The previously proposed structure for bicyclo-mahanimbine was based on analogy with cannabicyclol ;an X-ray study has established a revised structure for the latter compound and bicyclo-mahanimbine should accordingly be reformulated as (57).(j8 Me (57) (55) A C2 carbazole alkaloid subincanine from Aspidosperma subincanurn is clearly of an intriguing new type but insufficient material was available for complete structural elucidation ;the working structure (58) is proposed.69 Rox-burghine D,70isolated along with four diastereoisomers from Uncaria gambir also represents a new structural type derived from one C,,-monoterpenoid and two tryptamine units.Two structures are compatible with the spectroscopic (58) (59) 66 S. McLean and D. G. Murray Canad. J. Chem. 1970,48,867.67 (a)J. A. Joule Ann. Reports (B),1969,66,478; (6) N. S. Narasimhan M. V. Paradkar and S. L. Kelkar Indian J. Chem. 1970 8 473; (c) B. S. Joshi V. N. Kamat and D. H. Gawad Tetrahedron 1970 26 1475; (4D. P. Chakraborty A. Islam S. P. Basak and R. Das Chem. and Znd. 1970 593; (e) S. P. Kureel R. S. Kapil and S. P. Popli ibid. 958; (f)S. P. Kureel R. S. Kapil and S. P. Popli Experientia 1970 26 1055. 68 M. J. Begley D. G. Clarke L. Crombie and D. A. Whiting Chem. Comm. 1970 1547. 6q A. J. Gaskell and J. A. Joule Tetrahedron Letters 1970 77. 'O L. Merlini R. Mondelli G. Nasini and M. Hesse Tetrahedron 1970 26 2259. 480 H. F. Hodson evidence but one of these would contain a C, skeleton of a hitherto unencoun- tered type. The other formulation (59) contains a Corynanthd-type Cl0 unit and is thus preferred on biogenetic grounds ;moreover dihydrocorynantheine was also isolated from the same source.7o Corynantk-Strychohnos Alkaloids.-In a new modification of a well-known reaction tetrahydroalstonine has been prepared from (60) by reductive ring- closure under conditions mild enough for the ester group to remain intact.’ The reduction was effected by sodium borohydride in a two-phase system of methanol-ether-water containing sodium cyanide the initially-formed dihydro- compound being trapped as (61) and removed into the non-reducing ether-rich phase; acidification of (61) promoted loss of hydrogen cyanide followed by ring-closure.(60) (61) Ra~caffricine~’ from Rauwolja cafra is a D-( +)-galactoside of the indolenine alkaloid vomilenine.The particularly stable quaternary alkaloid hunteracine from Hunteria eburnea has been shown by X-ray analysis to have structure (62),7 which presumably arises by an N(btC(2) cyclisation of the stemmadenine- like hydroxyindolenine (63). Me (62) Dichotine (64; R = H) and 11-methoxydichotine (64;R = MeO) from Vallesia dichotoma have several novel features and display new and interesting chemical reactions. The structures (64) were established by X-ray crystallo- graph^,'^" but not before the major features had been recognised by an impressive 71 J. A. Beisler Chem. Ber. 1970 103 3360; cf. J. A. Beisler Tetrahedron 1970 26 1961 ;E. M. Fry and J. A. Beisler J. Org. Chem. 1970,35 2809. 72 M.A. Khan and A. M. Ahsan Tetrahedron Letters 1970 5137. ’3 R. H. Burnell A. Chapelle M. F. Khalil and P. H. Bird Chem. Comm. 1970 772. 74 (a)N. C. Ling C. Djerassi and P. G. Simpson J. Amer. Chem. SOC.,1970 92 222; (6)N. C. Ling and C. Djerassi ibid. 6019. Alkaloids 481 spectroscopic study of degradation products aided by isotopic labelling experi- ment~.'~~ As in vomicine and related alkaloids there is strong interaction (64 arrows) between N(b) and the carbonyl group leading to the formation at least in polar solvents of the zwitterion (65); the salts of course exist wholly in the form (66). A biogenesis from condylocarpine which also occurs in V. dichotoma seems likely and is to be tested. A second cyclic glyoxylamide acetal structure to be recognised during the year occurs in tsilanine (67; R' = H R2 = Me) and in three closely related alkaloids (67; R' = MeO R2 = Me; -0 *'&.Me I R1 RzOw (661 (67) R' = R2 = H; R' = MeO R2 = H) from Strychnos henningsii; confirmation of the proposed structures was provided by conversion of tsilanine into isoretuline obtainable from the Wieland-Gumlich aldeh~de.~' In a biogenetically inspired total synthesis of ajmali~~e~~ the key feature was the creation of an iminium ion (70) which could cyclise with formation of the C(16b C(5) bond.A mixture of diastereoisomers containing the desired tetracyclic aldehyde (68) formed by a glycol cleavage reaction was treated with a mixture of dicyclohexylcarbodi-imide and p-toluenesulphonic acid which promoted decarbonylation (69 arrows) to (70); spontaneous cyclisation then gave a H T 1 CHO H Me Et (68) (71) l5 R.Sarfati M. Pais and F-X. Jarreau Phytochemistry 1970,9 1107. '' E. E. van Tamelen and L. K. Oliver J. Amer. Chem. SOC. 1970,92,2136. 482 H. F. Hodson mixture from which (f)-deoxyajmalal B (71) was isolated. Resolution of this aldehyde was followed by epimerisation to deoxyajmalal A [71 C( 16)-epimer] which had previously been e~tablished~~ as a convenient relay compound for ajmaline synthesis by successive ring-closure and functionalisation at C(21). Aspidosperma and Ibogu Alkaloids.-The biogenetically unprecedented struc- tures earlier suggested (without stereochemistry) for ( +)-aspidodispennine (72; R = OH) and (-)-deoxyaspidodispermine (72; R = H) have been con- firmed by an X-ray study;” the absolute configuration followed from an 0.r.d.correlation with (-)-aspidospennine. Another addition to the highly charac- teristic Melodinus alkaloids is the hexacyclic meloscandonine (73) from M. scandens.’ Me & H Ac In two new synthetic approaches to the aspidosperma skeleton the last step was the formation through the 2-carbon bridge of ring E by an intramolecular alkylation at the /?-position of an indole. Thus the reaction between the tetra- cyclic ester (74; R = H) and ethylene dibromide gave (&)-minovine (75),*’ presumably via the indole (74; R = CH,CH,-Br); the starting ester (74; R = H) was obtained by an enamine annelation as shown to give (74; R = PhCH,) -a-I-I Me -J + O‘N P \Me’-1 ‘N Me C02Me Me COzMe (74) (75) 77 J.D. Hobson and J. G. McClusky J. Chem. SOC.(0,1967,2015. N. C. Ling and C. Djerassi Tetrahedron Letters 1970 301 5. 79 M. Plat M. Hachem-Mehri M. Koch U. Scheidegger and P. Potier Tetrahedron Letters 1970 3395. 8o F. E. Ziegler and E. B. Spitzner J. Amer. Chem. SOC.,1970 92 3492. Alkaloids 483 followed by debenzylation. In the other approach,'l which led to a 5-0x0-de-ethyl system [cf:(75)] the two-carbon bridge was provided by bromoacetyl bromide. The total synthesis of (f)-velbenamine has now been described in detaila2 and an intermediate in this synthesis the pentacyclic lactam (76) has also been converted into (*)-catharanthine (77).A series of paperss3 gives full details of OLJ Sq7 Me0 0 C02Me Me (76) (77) earlier reported partial83b (from catharanthine) and t~tal*~~~" syntheses of com- pounds of the cleavamine and 16-carbomethoxycleavamine series as well as to and their transannular cycli~ation~~" Aspido~perrna~~"~' Iboga' 3c types respectively. " C02Me (78) (82) (79; 16,17,15,20-tetrahydro) (83;15,2O-dehydro) (80;16,17-dihydro) (81;15,2O-dihydro) Skeletal Rearrangements-The name secodine is proposeda4" for the ester (78) which can be formally derived by simple reduction of the postulated key bio- synthetic intermediate' linking the CorynanthP-Strychnosalkaloids with the Aspidosperma and Iboga types. Further support for the suggested in vivo re-arrangement processess5 is now provided by the isolation from Rhazya spp.of alkaloids with the full carbon skeleton of (78).84 Tetrahydrosecodine (79) and a dihydrosecodine (80) from R. stricta and tetrahydrosecodin- 17-01 (82) from '' H-P. Husson C. Thal P. Potier and E. Wenkert Chem. Comm. 1970,480. '' G. Buchi P. Kulsa K. Ogasawara and R. L. Rosati J. Amer. Chem. Soc. 1970 92 999. 83 (a) J. P. Kutney E. Piers and R. T. Brown J. Amer. Chem. SOC.,1970 92 1700; (b) J. P. Kutney W. J. Cretney J. R. Hadfield E. S. Hall and V. R. Nelson ibid. p. 1704; (c)J. P. Kutney R. T. Brown E. Piers and J. R. Hadfield ibid. p. 1708; (6)J. P. Kutney W. J. Cretney P. LeQuesne B. McKague and E. Piers ibid.,p. 1712; (e) J. P. Kutney N. Abdurahman C. Gletsos P.LeQuesne E. Piers and I. Vlattas ibid. p. 1727. 84 (a) G. A. Cordell G. F. Smith and G. N. Smith Chem. Comm. 1970 189; (6) G. A. Cordell G. F. Smith and G. N. Smith ibid. p. 191. J. A. Joule Ann. Reports (B) 1968 65 501; ibid. 1969 p. 483; A. I. Scott Accounts Chem. Res. 1970 3 151. 484 H. F. Hodson R. orientalis were obtained only in small amounts after extensive fractionation procedures and the assigned structures were derived mainly by mass spectro- metry and confirmed by comparison with synthetic materials. (79)was syn- thesised86 as a mixture of diastereoisomers and used in an isotopic dilution method to demonstrate the natural occurrence of tetrahydrosecodine in R. orientalis ;86 [2-''C]tryptophan was incorporated to the remarkable extent of 0-5%.Independently of the above work 16,17-dihydrosecodin-17-01(83) was synthesiseds7 and was shown to be a natural constituent of R. orientalis by the incorporation of tritium-labelled loganin. The new alkaloids presecamine (84;R = X) and tetrahydropresecamine (84;R = Y) also from Rhazya spp. are Diels-Alder-type dimers of secodine (78) and 15,2O-dihydrosecodine (81); although structures (84)are preferred the less likely alternatives of type (85) cannot be excluded on the available evidence.84b Short-path distillation converts (84;R = X)and (84;R = Y)to the acrylic ester monomers (78)and (81)which on standing revert to the presecamines. Under mildly acidic conditions the presecamines rapidly and quantitatively rearrange to the corresponding secamines (86;R = X) and (86,R = Y) previously isolated" 7H ti COzMe (84) from Rhazya spp.The secamines may therefore be artefacts; moreover the unexpectedly low rotation of the presecamines suggests that these alkaloids are largely racemic at C-7 and C-16' and therefore may arise by non-enzymic dimerisation of secodine 86 R. T. Brown G. F. Smith K. S. J. Stapleford and D. A. Taylor Chem. Comm. 1970 190. " A. R. Battersby and A. K. Bhatnagar Chem. Comm. 1970 193. J. A. Joule Ann. Reports (B) 1968 65 501. Alkaloids 485 9 Terpenoid and Steroidal Alkaloids The nicotinoyl esters maytine (87; R = H) and maytoline (87; R = OH) from Maytenus ovatus are sesquiterpenoid bases of a novel type.89 X-Ray studies have shown that hetidi~~e,~' anhydroavignol," and miya- ~onitine,'~ all from Aconitum spp.are bases of the modified atisine type [c$ (89) with or without the N-C(6) bond] but a new variation of the atisine skeleton is HO. (88) (89) provided by delnudine (88)93 from Delphinium denudaturn; (88) could be bio-genetically derived from hetisine (89) by a route which includes the concerted rearrangement outlined (89 arrows).94 Me OMe (90) (91) 89 S. M. Kupchan R. M. Smith and R. F. Bryan J. Amer. Chem. SOC.,1970,92 6667. 90 S.W. Pelletier K. N. Iyer V. K. Bhalla M. G. Newton and R.Aneja Chem. Comm. 1970,393. " S. W. Pelletier S. W. Page and M. G. Newton Tetrahedron Letters 1970 4825. 92 H. Shimanouchi Y.Sasada and T. Takeda Tetrahedron Letters 1970,2327. 93 K.B. Birnbaurn Tetrahedron Letters 1969 5245. 94 M. Gotz and K. Wiesner Tetrahedron Letters 1969 5335. 486 H. F. Hodson The degradation product (90) of delphinine which could serve as a relay for the synthesis of the alkaloid itself has now been preparedg5" by a sequence which is the culmination of an extensive series of model experiment^.'^^ A novel 4-ketosteroidal amine solaphyllidine (91)96is related to the piper- ideinylpregnane precursors of the solanum and veratrum alkaloids. WjJ \ \ OH OH (92) (93) Me OMe Me -Me Rm-9 0, H 0 (96) H 10 Miscellaneous ( -)-Isoelaeocarpiline (92) has the absolute stereochemistry shown ; five new alkaloids from EIaeocarpa sphaerica are diastereoisomers of (92) but all have the same absolute configuration at C-16."7 (+)-Elaeocarpine (93) and (+)-iso- elaeocarpine (93; C-7 epimer) have been ~ynthesised.~~ The structures and (a)K.Wiesner E. W. K. Jay C. Demerson T. Kanno J. Krepinsky L. Poon T. Y. R. Tsai A. Vilim and C. S. Wu Experienria 1970 26 1030 (h) cf. J. A. Joule Ann. Reports (B) 1969 66. 487. A. Usubillaga C. Seelkopf I. L. Karle J. W. Daly and B. Witkop J. Amer. Chem. SOC.,1970 92 700. S. R. Johns J. A. Lamberton A. A. Sioumis H. Suares and R. I. Willing Chem. Comm. 1970 804. T. Tanaka and I. Lijima Tetrahedron Letters 1970 3963. Alkaloids 487 absolute configurations of stemonine (94)99and stemofoline (96),'0° both from Stemona japonica have been established by X-ray analysis ;protostemonine is (95)."' Two independent X-ray studies have shownlo2' that the absolute configuration of lunarine is the opposite of that arbitrarily selected earlier.'02b A basic constituent of Oncinotis inandensis is a mixture of (97) and its 13-0x0-isomer ;lo3' these alkaloids are closely related to the macrocyclic pyridine bases previously isolated'03b from 0.nitida.A base from Antirrhinum majus has been identified as 4-rnethyl-2,6-naphthyridine.l O4 99 H. Koyama and K. Oda J. Chem. Soc. (B),1970 1330. loo H. Irie N. Masaki K. Ohno K. Osaki T. Taga and S. Uyeo Chem. Comm. 1970 1066. lo' H. hie H. Harada K. Ohno T. Mizutani and S. Uyeo Chem. Comm. 1970 268. Io2 (a) J. A. D. Jeffreys and G. Ferguson J. Chem. SOC.(B) 1970 826; C. Tamura and G. A. Sim ibid.p. 991 :(h)J. D. Hobson Ann. Reports 1965.62 387. '03 (a)H. J. Veith M. Hesse and H. Schmid Helv. Chim. Acfu 1970 53 1355; (b)J. A. Joule Ann. Reports (B),1968 65 504. '04 K. J. Harkiss and D. Swift Tetrahedron Letters 1970,4773.

ISSN:0069-3030    

DOI:10.1039/OC9706700467

出版商:RSC    

年代:1970

数据来源: RSC

摘要:

15 Nucleic Acids By G. M. BLACKBURN Department of Chemistry The University Sheffield S3 7HF NINETEEN-SEVENTY heralded for some the ‘dawn of the second golden age of molecular biology” and for others the ‘Reversal of the Dogma’.2 The flow of information from DNA3 to RNA to protein is initially reversed for RNA tumour viruses whose information is transcribed from RNA into DNA.4,5 This has both justified Temin’s 1964 hypothesis6 concerning the induction of cancer by RNA viruses and stirred Crick to restate the central dogma of molecular biology’- essentially a negation of the possibility for information transfer from protein to nucleic acids. Crick’s new scheme’ represents three classes of relationship between the three groups of biopolymers (Figure 1).Transfers of information from DNA to DNA n LD N’88 ‘r :RNA-Pro kin \,A Figure 1 DNA to RNA and RNA to protein are widely supported by strong and direct evidence these are classed as general transfers. Special transfers do not occur in most cells but of three possible candidates RNA to RNA RNA to DNA and DNA to protein the first two have been observed in virus-infected cells. The dogma remains inviolate :information transfers from protein to protein protein to RNA and protein to DNA just do not happen. Other criticisms were levelled at orthodoxy by Don~hue,’.’~ who was con- cerned by the weakness in the crystallographic evidence supporting Watson-Crick ’ B. Lewin Nature 1970 227 1009. Editorial Nature 1970 226 1198. Abbreviations used are in accord with the recommendation of the IUPAC-IUA Commission J.Biol. Chem. 1970 245 5171. ‘D. Baltimore Nature 1970 226 1209. H. M. Temin and S. Mizutani Nature 1970 226 1211. H. M. Temin Nat. Cancer Inst. Monograph 1964 17 557. ’ F. H. C. Crick Cold Spring Harbor Symp. Exptl. Biol. 1958 12 138. F. H. C. Crick Nafure 1970 227 561. J. Donohue Science 1969 165 1091. lo J. Donohue Science 1970 167 1700. 490 G. M. Blackburn base-pairing in the double helix and by Commoner,'' who still declared that the biochemical specificity of proteins arises partly in protein and partly in DNA. These doubts were fully dispersed by Wilkins" and Arnott13 and by Fleischman14 and Hershey15 leaving Crick to prognosticate on the shape of things to come and proselytise on behalf of a biochemical theology.His light- hearted lecture,16 'Molecular Biology in the Year 2000' evoked a piece of veritable Pi in the High.17 The outstanding achievements of the last two years were the synthesis of a gene by Khorana's team18 and the isolation of the DNA of a single operon by Beckwith's group.lg In the ribonucleic acid field great progress has been made in the determination of the sequences of the viruses Q/120 and R17,21-23and the role of poly 1-polyC as a stimulator of interferon production24 even found applica- tion against rabies.25 Kornberg's DNA polymerase experienced fluctuating fortunes as it was relegated from being the DNA replicating enzyme26 to the repairer of damaged DNA2' in a multi-enzyme while a new candidate emerged for the role of repli~ase.~' It was not these upheavals but recollections of an earlier generation of molecular biologists which prompted Waddington to write3' '.. . Perhaps it is legitimate to remark that young Turks look younger or more Turkish or what have you if the conclusions they eventually reach are different from what anyone had said before them.' However the text of the year was surely given by Hershey." '. . .Not even DNA structure is inherited only hereditary principles are inherited for example nucleotide sequences.' I' B. Commoner Nature 1968 220 334. M. F. H. Wilkins S. Arnott D. A. Marvin and L. D. Hamilton Science 1970 167 1693. l3 S. Arnott Science 1970 167 1694. l4 P. Fleischman Nature 1970 225 30.l5 A. D. Hershey Nature 1970 226 697. l6 F.H. C. Crick Nature 1970 228. 613. " A. G. Ogston Nature 1970 228 1121. K. L. Agarwal H. Biichi M. H. Caruthers N. Gupta H. G. Khorana K. Kleppe A. Kumar E. Ohtsuka U. L. RajBhandary J. H. van de Sande V. Sgaramella H. Weber and T. Yamada Nature 1970 227 27. l9 J. Shapiro L. Machattie L. Eron G. Ihler K. Ippen and J. Beckwith Nature 1969 224 768. 2o M. A. Billeter J. E. Dahlberg H. M. Goodman J. Hindley and C. Weissmann Nature 1969 224 1083. J M. Adams P. G. N. Jeppesen F. Sanger and B. G. Barrel] Nature 1969,223 1009. 22 J. Argetsinger Steitz Nature 1969 224 957. 23 P. G. N. Jeppesen J. A. Steitz R. F. Gesteland and P. F. Spahr Nature 1970,226,230. 24 T. C. Merigan Nature 1970 228 219. 25 P.Fenje and B. Postic Nature 1970 226 171. 26 A. Kornberg Science 1969 163 1410. " R. B. Kelly M. R. Atkinson J. A. Huberman and A. Kornberg Nature 1969 224 495. E. M. Witkin Nature New Biol. 1971 229 81. 29 A. Klein and U. Niebch Nature New Biol. 1971 229 82. 30 R. Knippers Nature 1970 228 1050. " C. H. Waddington Nature 1969 221 318. Nucleic Ac ids 49 1 1 Prebiotic Chemistry This has been a popular field for reviewer^^^-^' notwithstanding the yawning gaps for some of the unit steps in ab initio formation of biological polymers. Microwave radioastronomy has identified ammonia,36 water,37 and formalde- hyde3* in cool regions of the galaxy which are thought to be clouds of dust and gas contracting to give birth to new stars and planetary systems.Since the presence of formaldehyde is taken as indirect evidence for methane. with hydrogen hydrogen cyanide and carbon monoxide already identified it appears that interstellar clouds may contain most of the elementary compounds which have almost literally ‘sparked off’ prebiotic synthetic studies. The attraction of some of the models for prebiotic phosphorylation have palled as trimetaphosphate salts appear to give 2’(3’)-ribonucleoside phosphates rather than the 5’-isomers3 and the thermodynamics of phosphorylation by cyano- 9940 vinyl phosphate looks rather unfa~ourable.~’ Perhaps more attention should be directed towards those reagents which are known to exhibit a preference for phosphorylation of the primary hydroxy-f~nction,4~~~ particularly in the light of Ts’o’s interesting discovery p-imidazolyl-4(5)-propanoicacid catalyses the polymerisation of 5’-deoxynucleotides with specific formation of the natural 3’ -P 5‘ phosphate linkage.45 Two models for the nucleotide-linked synthesis of peptides have used the properties of amino-acid adenylate anhydrides in aqueous systems.One makes to use of ~arbodi-imide~~ give ‘proteinoids’ while the second adopts 0-+ I 2NH3CHMeCOO-P-O-Adenosine -+ II 0-0 I NH,CHMeCONHCHMeCOO-P-0-Adenosine + AMP II 0 32 M. Calvin ‘Molecular Evolution towards the Origin of Living Systems on the Earth and Elsewhere’ Clarendon Press Oxford 1969. 33 D. H. Kenyon and G. Steinman ‘Biochemical Predestination’ McGraw-Hill Co. New York 1969.34 R. M. Lemmon Chem. Rev. 1970 70 95. A. I. Oparin ‘Genesis and Evolutionary Development of Life’ Academic Press New York 1969. 36 A. C. Cheung D. M. Rank C. H. Townes D. D. Thornton and W. J. Welch Phys. Rev. Letters 1968 21 1701. 37 A. C. Cheung D. M. Rank C. H. Townes D. D. Thornton and W. J. Welch Nature 1969 221 626. 38 L. E. Snyder D. Buhl. B. Zuckerman and P. Palmer Phys. Reo. Letters 1969 22 679. 39 A. W. Schwartz Chem. Comm. 1969 1393. 40 R. Saffhill J. Org. Chem. 1970 35 281 1. 41 J. P. Ferris G. Goldstein and D. J. Beaulieu J. Amer. Chem. Soc. 1970 92 6598. 42 K.-I. Imai S. Fujii K. Takanohashi Y. Furukawa T. Masuda and M. Honjo J Org. Chem. 1969 34 1547. 43 0. Mitsunabu K. Koto and J. Kimura J. Amer. Chem. SOC.,1969 91 6510.44 M. Yoshikawa T. Kato and T. Takenishi Tetrahedron Letters 1967 50 5065. 45 0. Pongs and P. 0. P. Ts’o Biochem. Biophys. Res. Comm. 1969 36 475. *‘ G. Krampitz and S. W. Fox Proc. Nut. Acad. Sci. U.S.A. 1969 62 399. G. M. Blackburn montmorillonite clays:' which adsorb amino-acid adenylates better than either of their hydrolysis products AMP and amino-acids. This heterogeneous system has two attractive features :first the initiation process (1)involves the interaction of two amino-acid adenylates in contrast to condensations in homogeneous solution which are initiated by attack of a free amino-acid on the anhydride. Secondly the yield of oligopeptide products does not show the usual exponential decline with increasing chain length but indicates a preference for multiples of nonamers polyalanine of molecular weight 4OOO accounting for some 10per cent of the starting material.It is interesting to record that a recent high-yielding pep- tide synthetic method is apparently based on a phosphate-carboxylate type of anhydride.48 2 Bases Nucleosides and Nucleotides Dewar has applied semi-empirical SCF-MO calculations to determine the preferred tautomeric forms of the nucleic acid bases A C G and U.49In agree- ment with all previous studies the lactam-amine forms emerge more favoured than the lactim-imine tautomers. Cytosine is much the most mutable system with only 2.2kcal mol- separating the amino- and imino-forms. This coupled with the loss of one hydrogen bond (about 3 kcal mol-') in changing from a C-G to a C*-A base pair provides a value for this spontaneous mutation of S4kcal mol-' which is in nice agreement with a genetically estimated value.50 The search continues for reagents which can modify efficiently only one of the nucleic acid bases.Ethyl N-hydroxycarbamate which is a metabolite of the equally carcinogenic ethyl carbamate reacts with cytosine forming an N4-acyl derivative which is readily hydrolysed to uracil. The hydrolysis products of DNA treated with this reagent contain 2'-deoxyuridine and its 5'-phosphate ethyl carbamate does not generate these product^.^ Diethyl pyrocarbonate ruptures the pyrimidine ring in adenine,5 hydroxylamine-0-sulphonicacid converts guanosine and inosine into their N'-amino derivative^,^ and ethylen- imine achieves the unexpected transformation of 4-thiouridine (1) into N4-[2-(j?-R H R R I I I A *y"O,,NaHSO I ''3- N\ FIN,)-HNCH,CH, S SO,H S (1) H,NCH,CH,' R = ribosyl (3) (2) 47 M.Paecht-Horowitz J. Berger and A. Katchalsky Nature 1970 228 636. 48 G. Gawne G. W. Kenner and R. C. Sheppard J. Amer. Chem. SOC.,1969,91 5669. 49 N. Bodor M. J. S. Dewar and A. J. Harget J. Amer. Chem. SOC.,1970 92 2929. 50 M. W. Strickberger 'Genetics' Macmillan & Co. Ltd. New York 1968. 51 R. Nery J. Chem. SOC.(0,1969 1860. 52 N. J. Leonard J. J. McDonald and M. E. Reichmann Proc. Nat. Acad. Sci. U.S.A. 1970 67 93. 53 A. D. Broom and R. K. Robins J. Org. Chem. 1969 34 1025. Nucleic Acids 493 aminoethylthio)ethyl]cytidine (2) with a similar effect on 2-thiopyrimidine nucleo~ides.~~ The use of deuterium isotopic substitution provides further details of the mode of action of hydr~xylamine~~ and of N'-methyl-N3-nitro-N1-nitrosoguanidine on the bases.Since the latter alkylates DNA in vitro with retention of all three methyl-hydrogen atoms shown by the isolation of 7-tri-deuteriomethylguanine its mutagenic effect must result from direct methyl transfer rather than from the generation of diaz~methane.~~ Encouraged by the ob~ervation~~ that 4-thiouridine (1) is oxidised by air in bisulphite buffers to the pyrimidine sulphonic acid (3) two research groups have observed that the reversible addition of bisulphite to the 5,6-double bond of uracil or cytosine facilitates reactions at C-4 such as the deaminatior~~~~~~ and transamination6' of cytosine.The stereochemistry and kinetics of addition of bisu1phite6l suggest that the same mechanism operates as for the addition of methoxylamine to ~ytidine.~ Bisulphite buffers also catalyse the decarboxylation of 5-carboxyuracil and its derivatives.62 In bacterial systems bisulphite produces mutations ten times faster than the spontaneous rate,6 which are shown by reversion analysis to be specifically GC -+ A-T transition^.^^ The position of sulphur dioxide as a food additive and as an atmospheric pollutant will no doubt receive further attention. Perhaps the simplest way of achieving a C +T transition results from the radioactive decay of 5-[3H]-cytosine.65 While this is as yet detectable only by mutational techniques it apparently proceeds with 100 per cent efficiency.Although the C(5)-hydrogen of uridines is readily exchanged in alkaline con- dition~,~~,~~ isotopic hydrogen exchange in DNA proceeds with general base catalysis68 and can be restricted to purine^.^' Specific isotopic syntheses have been reported for cytidine C-tritiated in the ribose moiety,70 for ['4C]methyl labelled th~rnidine,~ and for three '80-labelled adenosines.' Structures have been assigned for several nucleoside-like metabolites. Sparso- mycin7 is a derivative of 5-(~-acrylamide)-6-methyluracil(4), and further analysis 54 B. R. Reid Biochemistry 1970 9 2852. 55 D. M. Brown and P. F. Coe Chem. Comm. 1970 568. 56 R. Haerlin R.Sussmuth and F. Lingens F.E.B.S. Letters 1970 9 175. '' H. Hayatsu J. Amer. Chem. Soc. 1969 91 5693. 58 H. Hayatsu Y. Wataya K. Kai and S. Iida Biochemistry 1970 9 2858. 59 R. Shapiro B. I. Cohen and R. E. Servis Nature 1970 227 1047. 6o R. Shapiro and J. M. Weisgras Biochem. Biophys. Res. Comm. 1970 40 839. " R. Shapiro R. E. Servis and M. Welcher J. Amer. Chem. Soc. 1970 92 422. '2 K. Isono,S. Suzuki M. Tanaka J. Nanbata and K. Shibuya Tetrahedron Letters 1970 425. 63 H. Hayatsu and A. Miura Biochem. Biophys. Res. Comm. 1970 39 156. '4 F. Mukai I. Hawryluk and R. Shapiro Biochem. Biophys. Res. Comm. 1970,39,983. 65 F. Funk and S. Person Science 1969 166 1629. 66 S. R. Heller Biochem. Biophys. Res. Comm. 1968 32 998. 67 D. V. Santi C. F. Brewer and D.Faber J. Heterocyclic Chem. 1970 7 903. 68 B. McConnell and P. H. von Hippel J. Mol. Biol. 1970 50 297. 69 F. Doppler-Bernardi and G. Felsenfeld Biopolymers 1969 8 733. 'O U. Brodbeck and J. G. Moffatt J. Org. Chem. 1970 35 3552. 71 L. Pichat B. Masse J. Deschamps and P. Dufay Compt. rend. 1969 268C 197. 72 H. Follman and H. P. C. Hogenkamp J. Amer. Chem. SOC. 1970 92 671. 73 P. F. Wiley and F. A. MacKeller J. Amer. Chem. SOC. 1970 92 417. G. M. Blackburn of nucleocidin has found it to contain fluorine :4’-fluoroadenosyl5’-sulphamate is the revised structure.74 Other novel derivatives of adenosine include an insecticidal endotoxin’ from Bacillus thuringiensis (5)and the hypercholesterol- emic compound lentysine otherwise known as eritadenine which is isolated from the Japanese mushroom Shiitake and whose structure (6)has been estab- lished by ~ynthesis.~~-~~ A minor base component of tRNA from both yeastSo and plant” sources is the urea derived from threonine and adenine (7).OH OH (4) (5) HO OH A large volume could be written about syntheses of these and other modified nucleosides which might almost refer to every permutation of the substitution by carbon nitrogen or sulphur for one or other of the pentose oxygens-in all possible configurations. Most such syntheses rely on well-tried methods which ’4 G. 0. Morton J. E. Lancaster G. E. Van Lear W. Fulmer and W. E. Meyer J. Amer. Chem. SOC.,1969,91 1535. 7s J. FarkaS K. Sebesta K. Horska 2.Samek L. DolejS and F.Sorm Coll. Czech. Chem. Comm. 1969 34 1118. 76 T. Kamiya Y. Saito M. Hashimoto and H. Seki Tetrahedron Letters 1969 4727. 77 M. Hashimoto Y. Saito H. Seki and T. Kamiya Tetrahedron Letters 1970 1359. ”K. Okumura T. Oine Y. Yamada M. Tomie T. Nagura M. Kawazu T. Misoguchi and I. Inoue Chem. Comm. 1970 1045. 79 M. Kazawu T. Kanno N. Takamura T. Misoguchi S. Saito and K. Okumura Chem. Comm. 1970 1047. ‘O G. B. Chheda R. D. Hall D. I. Magrath M. P. Schweizer L. Stasiuk and P. R. Taylor Biochemistry 1969 8 3278. 8’ W. H. Dyson C. M. Chen S. N. Alam R. H. Hall C. I. Hong and G. B. Chheda Science 1970 170 328. Nucleic Acids 495 only rarely produce the unusual e.g. the interrelation of nucleic acids with the distant field of 1,3-dipolar addition reactionss2 or of norbornene chemistry.83 A few carefully-planned objectives in enzyme mechanisms have produced inter- esting results such as the conversion of norbornadiene into the aminocyclo- pentane(8) which is fed into the synthesis of a carbocyclicanalogue of adenosine,84 and further transf~rmed~~ into the coenzyme B, analogue (9).This analogue \ (8) (k) HO/ OH (9) substitutes adequately for the native coenzyme in the B ,,-dependent dioldehyd- rase reaction. Hence Abeles argues the enzyme mechanism does not require the adenosine 5’-methylene group to develop anionic character in the transition state. This conclusion fits the result of deuterium exchange in the B ,-dependent enzymic rearrangement of methylmalonyl coenzyme A to succinyl CoA which implicates the displacement ofcobalt by a hydrogen atom so that there are three equivalent hydrogens presumably on the 5’-position of 5’-deo~yadenosine.~~ Much the same permutations and combinations have been made in synthetic nucleotide chemistry where the use of analogues as therapeutic agents” and as tools in nucleic acid researchg8 has been reviewed.Here substitutions of phos-phate oxygens have provided a plentiful supply of ph~sphonate,~’ amidateyo*’’ and phosph~rothioate’~~~~ phosphor-nucleotide analogues though the behaviour of these compounds as enzyme substrates is frequently either too predictable or too equivocal for them to assist in the unravelling of the enzyme mechanism. This approach was made applicable to the mechanism of action of ribonuclease through the X-ray elucidation of the structure of crystalline uridine 2‘,3‘-00-cyclophosphorothioate,94which has the R-configuration at phosphorus (10).” E. M. Acton K. J. Ryan and L. Goodman Chem. Comm. 1970 313. 83 Y. F. Shealy and C. A. O’Dell Tetrahedron Letters 1969 2231. 84 Y. F. Shealy and J. D. Clayton J. Amer. Chem. SOC.,1969 91 3075. 8s S. S. Kerwar T. A. Smith and R. H. Abeles J. Biol. Chem. 1970 245 1169. ’‘ W. M. Miller and J. H. Richards J. Amer. Chem. SOC.,1969 91 1498. ” T. Y. Shen Angew. Chem. Internat. Edn. 1970 9 678. ” F. Cramer Accounts Chem. Res. 1969 2 338. ‘9 G. H. Jones H. P. Albrecht N. P. Damodaran and J. G. Moffatt J. Amer. Chem. Sac. 1970 92 5510. 90 B. Jasdorf and H. Hettler Chem.Ber. 1969 102 4119. 91 R. L. Letsinger and W. S. Mungell J. Org. Chem. 1970 35 3800. 92 A. F. Cook J. Amer. Chem. SOC.,1970 92 190. ” F. Eckstein J. Amer. Chem. SOC., 1970 92 4718. 94 W. Saenger and F. Eckstein J. Amer. Chem. SOC. 1970 92 4712. 496 G. M. Blackburn The hydrolysis of this substrate by ribonuclease in 80-enriched water provided the isotopically-labelled uridine 3'-phosphorothioate (1 1). This was dehydrated by use of diethyl phosphorochloridate and provided a mixture of the original crystalline cyclic phosphorothioate (10)with loss of H,' *Oand the non-crystalline diastereoisomer (12) with retention of the oxygen isotope. It follows that the H (Eto),POCI -(10) (11) (12) enzymic hydrolysis and the chemical dehydration must pass through transition states of similar geometry which in the latter case can be predicted by application of Westheimer's preference rules for pseud~rotation.~~ The stereochemistry of ribonuclease-catalysed hydrolysis of the cyclic phos- phorothioate(10)thus appears to involve 'in line'displacement of the 2'-oxygen by water.96 This hard-won conclusion supports the earliest suggested mechanism for this enzyme9' and accords well with the disposition of catalytic functions in the active site of crystalline ribon~clease.~~ Spectroscopic methods have been used to probe deeper into the details of nucleoside and nucleotide structure.Miles and Eyring have a new theory for the optical activity of pyrimidine nucleosides based on their analysis of 38 nucleoside c.d.spe~tra.~~.'~~ They opt for a bond-bond coupled-oscillatory theory which gives a satisfactory account of most of the observed optical proper- ties."' High resolution 'H n.m.r. studies provide evidence for ribose conforma- tions of nucleosides in solution largely by spin-spin coupling analyses,lo2-' O4 and Nuclear Overhauser Effects have illuminated new aspects of the conforma- tions of the glycosidic bond in purine nucle~sides.'*~ A thorough analysis of NAD' NADH and some analogues reveals chemical shifts due to the effect of aromatic ring currents. The evidence favours two folded 95 F. H. Westheimer Accounts Chem. Res. 1968 1 70. 96 D. A. Usher D. I. Richardson and F. Eckstein Nature 1970 228 663. 91 D. Findlay D.G. Herries A. P. Mathias B. R. Rabin and C. A. Ross Nature 1961 190 781. 98 H. Wyckoff K. D. Hardman N. M. Allewell T. Inagami L. N. Johnson and F. M. Richards J. Biol. Chem. 1967 242 3984 3749. 99 D. W. Miles M. J. Robins R. K. Robins M. W. Winkley and H. Eyring J. Amer. Chem. Sac. 1969 91 824 831. 100 D. W. Miles W. K. Inskeep M. J. Robins M. W. Winkley R. K. Robins and H. Eyring J. Amer. Chem. SOC.,1970 92 3872. I01 W. H. Inskeep D. W. Miles and H. Eyring J. Amer. Chem. SOC. 1970 92 3866. I02 F. E. Hruska A. A. Grey and I. C. P. Smith J. Amer. Chem. Soc. 1970 92 4088. 103 D. B. Davies Nature New Biol. 1971 229 3. 104 R. H. Sarma and N. 0. Kaplan Biochemistry 1970 9 557. 105 P. A. Hart and J. P. Davies J. Amer. Chem. SOC. 1969 91 512. Nucleic Acids 497 conformations for the dinucleotide in aqueous solution with the adenine and pyridine rings stacked in right-handed and left-handed conformations that are in rapid equilibrium.104*106*107 When NAD' was bound to lactate dehydrogen- ase very similar shifts were observed which were interpreted along with other evidence to favour the binding of folded coenzyme to the enzyme."* Unfor-tunately that conclusion is at variance with the X-ray structure of lactate dehydr~genase"~ which shows that NAD+ lies in a groove in the protein in its extended conformation with the adenine and pyridine groups at maximum separation. Unless the enzymes from chicken heart and dogfish have funda- mentally different structures it appears that aromatic groups in the enzyme generate magnetic anisotropy around the nicotinamide in the extended conforma- tion of the coenzyme which is fortuitously similar to that effected by the adenine n-system in the folded conformation-a chance coincidence recognised and dis- counted by Kaplan.The l3C-magnetic resonance of nucleosides' lo and nucleotides' ' has been studied at natural abundance of this isotope and appears likely to provide useful information about the n-electron distribution in the bases as well as locating the positions of substituents.' l2 Progress in the application of mass spectrometry has been slow. While the accumulation of standard spectra of nucleosides' will ensure its future use for the identification of structural features such as C-nucleosides,' l4 the results obtained on dinucleoside phosphates,' ' labelled with phenyl borate at the 3'-end and volatilised by trimethylsilylation fail to give the impression that mass spectro- metry will contribute to the sequencing of oligonucleotides as successfully as it has for oligopeptides.3 Oligonucleotides Synthesis of ribonucleotides is still locked at the trimer stage beset partly by the extra dimension introduced in providing protecting groups for the 2'-hydroxy- functions and partly by the lack of objectives which cannot be attained better by the combination of chemical oligodeoxynucleotide synthesis with enzymic transcription into RNA. Neilson' ' demonstrates chain synthesis by adding phosphates to the 3'-hydroxy-function of a protected nucleoside by a triester route to make U-U-U while Holy builds the chain in the opposite direction by lob R.H. Sarma and N. 0. Kaplan Biochemistry 1970 9 539. lo' R. H. Sarma M. Moore and N. 0. Kaplan Biochemistry 1970 9 549. R. H. Sarma and N. 0. Kaplan Proc. Nut. Acad. Sci. U.S.A. 1970 67 1375. M. J. Adams A. McPherson M. G. Rossmann R.W. Schevitz and A. J. Wonacott J. Mol. Biol. 1970 51 31. 'lo A. J. Jones D. M. Grant M. W. Winkley and R. K. Robins J. Amer. Chem. SOC. 1970 92 4079. ''I D. E. Dorman and J. D. Roberts Proc. Nat. Acud. Sci. U.S.A. 1970 65 19. 'I2 A. J. Jones M. W. Winkley and D. M. Grant Tetrahedron Letters 1969 5197. 'I3 S. J. Shaw D. M. Desiderio K. Tsuboyama and J. A. McCloskey J. Amer. Chem. SOC., 1970 92 2510. 'I4 J. M. Rice and G.0.Dudek Biochem. Biophys. Res. Comm. 1969 35 383. 'Is J. J. Dolhun and J. L. Wiebers J. Amer. Chem. SOC.,1969 91 7755. T. Neilson Chem. Comm. 1969 1139. G. M. Blackburn the addition of protected nucleoside 3'-phosphates to the 5'-hydroxy-group of the foundation nucleoside' in the synthesis of G4-C and 36 other trinucleo- side diphosphates. An unusual approach to synthesis ofdeoxynucleotides uses the reaction between deoxynucleoside 3'-phosphorofluoridates and the 5'-OH group under the in- fluence of strong base in dimethyl formamide solution :good yields are obtained for d(T-T) d(A-T) and d(T-T-T).'I8 The protection of a terminal phosphate monoester function through the course of oligomer synthesis has been improved by the use of anisidine which gives a phosphoramidate susceptible to cleavage by isoamylnitrite,' '9,120of 4-chloro-2-nitrophen01,~~ ' or of a variety of 2-sub- stituted ethan~ls.'~~-'~~ One of these 2-(2-pyridyl)ethanol also functions as the point of attachment for phosphates to a polymer support'25 in a synthesis of d(pT-T-T-T-T-T).Although other insoluble support systems have been used in the synthesis of penta-'26 and he~a-thymidyl'~' oligodeoxynucleotides these and the soluble polymer systems'28 must now be virtually obsolete for nucleotide synthesis. A novel application for polymer supports has been illustrated by a study of the mechanisms of phosphodiester synthesis involving carbodi-imides and aryl- sulphonyl chloride reagents. It appears that there is no simple role for monoalkyl metaphosphate in either case.' 29 An examination of phosphorylation inter- mediates by 31Pn.m.r.suggests that symmetrical pyrophosphates intervene in the synthesis of phosphate triesters in the presence of tri-isopropylbenzenesulphonyl ~hloride.'~' In five years Khorana's magnum opus has reached its first objective the total synthesis of a gene.' In 1965 the only gene of defined chemical composition was that corresponding to the principal yeast alanine tRNA whose structure had been determined by H~lley.'~' The relation between the tRNA sequence and the DNA gene are shown in Figure 2. The antiparallel DNA strands are segmented into fifteen oligodeoxynucleotides whose synthesis by well-proved methods was the first stage of the project.These methods have changed little of late and were 'I7 A. Holy Coil. Czech. Chem. Comm. 1970 35 3686. I" * R. von Tigerstrom and M. Smith Science 1970 167 1266. E. Ohtsuka K. Murao M. Ubasawa and M. Ikehara J. Amer. Chem. SOC. 1970,92 344 1. E. Ohtsuka M. Ubasawa and M. Ikehara J. Amer. Chem. SOC.,1970 92 5507. ''I S. A. Narang 0.S. Bhanot J. Goodchild and R. H. Wightman Chem. Cumm.,1970,91. ILZ S. A. Narang 0. S. Bhanot J. Goodchild J. Michniewicz R. H. Wightman and S. K. Dheer Chem. Comm. 1970 516. L23 W. Freist R. Helbig and F. Cramer Chem. Ber. 1970 103 1032. W. Freist and F. Cramer Chem. Ber. 1970 103 3122. lLS W. Freist and F. Cramer Angew. Chem. Internat. Edn. 1970 9 368. L. R. Melby and D. R. Strobach J.Org. Chem. 1969 34 421. 12' T. Kusame and H. Hayatsu Chem. and Pharm. Bull (Japan) 1970 18 319. IZ8 See reference 8 of reference 127. G. M. Blackburn M. J. Brown M. R. Harris and D. J. Shire J. Chem. SOC.(0, 1969 676. I3O F. Eckstein and D. Rizk Chem. Ber. 1969 102 2362. ''I R. W. Holley J. Apgar G. A. Everett J. T. Madison N. Marquisee S. H. Merrill J. R. Penswick and A. Zamir Science 1965 147 1462. 5'-ribo 3 I -deoxy 5 -deoxy 5 -rib0 3 -deoxy 5 -deoxy 5 -rib 3 -deoxy 5 -deoxy 5 -deoxy 30 1 10 20 m 2 G-G-G-C-G-U-G-U-~-G-C-G-C-G-U-A-G-D-C-G-G-D-A-G-C-G-C-G-C-U-C-C--[nI---- -[H-Iil-C-C-C-G-C-A-C-A-C-C-G-C G-C-A-T-C-A-G-C-C-A T-C-G-C-G-C-G-A-G-G 1l111111111111l11111lllllll (111) G-G-G-C-G-T-G T-G-G-C-G-C-G-T-A-G T-C-G-G-T-A-G-C-G-C -[c)l-[m]-[k]-30 40 50 60 m 2 -G-C-U-C-C-C-U-U-I-G-C-~-~-G-G-G-A-G-A-G-D-C-U-C-C-G-G-T-~-C-G-A-U-U-G-A-A-T-C G-T-A-C-C-C-T-C-T-C-A-G-A-G-G-C-C-A-A-G 1111111111111111111111111 G-C-T-C-C-C-T-T-A-G-C-A-T-G-G-G A-G-A-G-T-C-T C-C-G-G-T-T-C-G-A-T-T (11) I J [hI --[gl--el-60 70 77 -G-A-U-U-C-C-G-G-A-C-U-C-G-U-C-C-A-C-C-A 3 -ribo 11 1 ---~dJ---I a]* C-T-A-A-G-G-C-C T-G-A-G-C-A-G-G-T-G-G-T 1111111111111111 C-C-G-G-A-C-T-C-G-T C-C-A-C-C-A (1) -[c]-[b]-Figure 2 T-T-A-A-T-T-A-C-A-A-T-A A-T-T-T-T-C-C-A-A-T-T-G A-T-A-C-A-A-A-C-T-A-C-A I II IL J Figure 3 500 G.M. Blackburn illustrated by the preparation of the eicosadeoxynucleotide (Figure 2f) which was described in the 1968 report.’32 The second stage involved the enzymic coupling of the segments into three subgroups to give the double-stranded polymers (I) (11) and (111).This can be achieved by the phosphorylation of the 5’-hydroxy-terminus of the shorter seg- ments using ATP and an enzyme. The segments are then correctly aligned on annealing by virtue of their inherent ability to base-pair with complementary sections of the opposite strand. Lastly this assembly is covalently linked from 5’-phosphate to 3’-hydroxy-groups by the ligase enzyme. In the case of (11) the 5’-ends of segments e g and i were phosphorylated independently before mixing nanomolar amounts of segments f-i. Annealing the mixture results in correct interaction of the segments to give a single unit which is for the most part double-stranded and has one ‘nick’ in each strand These nicks were sealed by the ligase enzyme after which the remaining segment e was added annealed into position and the nick between residues 5&51 efficiently welded by the enzyme to give (11).Initial attempts to make (I) by the simultaneous linking of a to d and of b to c failed because the C-C-G-G-end of c is able to complement onto itself which resulted in the formation of a dimer of sequence a-c-b. This was circumvented by joining a to d in the presence of c which was not phosphorylated at its 5’-terminus so that the covalent linkage of the 5’-terminal cytidine of c to the 3’-terminal thymidine of a was precluded. The fragment a-d was combined with phosphorylated b and c and enzymically joined to give (I).Although the high C + G content of (111) posed further prob- lems they were eventually surmounted so that the unified segment (111) containing units k-o was obtained in 6&70 per cent yield. The completion of the total synthesis of the gene was accomplished by two routes the one adding (111) to the combined (I) and (11) the other joining (11) and (111) before adding (I). In the former the ligase welded (I) to (11) in 60 per cent yield before this large unit was annealed with (111) and segment j. The final enzymic sealing of the nicks proceeded with about 65 per cent efficiency to give the synthetic gene. Throughout the latter two stages of the synthesis the efficiency of the joining processes were monitored by the use of both 32Pand 33Ptracers at high and low levels of activity and much of the oligonucleotide purification depended on gel- filtration techniques.Khorana now expects to replicate this gene using DNA polymerase to provide a stable adequate supply of the DNA for future use especially for its transcription with RNA polymerase. This is anticipated to provide an RNA which ought to be a precursor of the tRNAA’” and which ought to be convertible into the mature tRNA by enzymic modification of the appropriate A G and U bases. Whether the product will be identical with Holley’s tRNAA’” is a moot point since criticisms of the correctness of the assigned’ sequence have been made.’33*134Fortunately one of the residues in question lies in the variable 13’ G.M. Blackburn and M. J. Waring Ann. Reports 1968 65B,535. 133 M. B. Shapiro C. R. Merril D. F. Bradley and J. E. Mosimann Science 1965 150 918. 134 C.R. Merril Biopolvmers. 1968. 6.1727. Nucleic Acids 501 loop of the general tRNA structure (p. 509) where it is unlikely to influence the tertiary structure of the synthetic immature tRNA. Narang has prepared two further dodecadeoxynucleotides.l These now 3291 complete the subunits required for a single strand (Figure 3) of the DNA helix which codes for half the gene of bovine insulin chain A corresponding to amino- acids 11-21 plus a terminator signal. The discovery that insulin is derived from a single-chain biosynthetic precursor pro-in~ulin,'~~ of 84amino-acids somewhat increases the problem of synthesis of this gene.4 Photochemistry Cyclobutane products continue to hold centre-stage in nucleic acid photochem- istry. The X-ray analyses of structures for several photodimers have confirmed earlier structural assignments. The cyclobutane ring is found to be planar only in the centrosymmetric dimers such as the trans-anti thymine dirnerl3' (13) and is puckered for other isomers.' *-14' An exception to this generalisation is provided by the cis-syn dimer of 1,l'-trimethylenedithymine (14)which also has 0 0$O HN* 0 a planar cyclobutane ring.'42 The structures of all four uracil dimers have been confirmed by synthesis from the dianhydrides of the all-cis- and cis,trans,cis- cyclobutane-1,2,3,4-tetracarboxylic acids.1437 144 The mechanisms of photodimerisation of pyrimidines in aqueous solution have been explored in detail by Johns.' 45 The model that emerges for thymine dimer- isation at low concentration in quoinvolves collision of triplet and ground state molecules though the process has only two per cent efficiency.Temperature affects the ratio of the four stereoisomers but not the gross yield of products. In concentrated solution dimerisation proceeds from aggregates principally dimers 135 S. A. Narang and S. K. Dheer Biochemistry 1969 8 3443. 136 R. E. Chance R. M. E. Ellis and W. M. Bromer Science 1968 161 165. 13' N. Camerman and S. C. Nyburg Actu Cryst. 1970 B25 388. 138 N. Camerman D. Weinblum and S. C. Nyburg J. Amer. Chem. SOC. 1969 91 982. 139 E.Adman and L. A. Jensen Acta Cryst. 1970 326 1326. 140 N. Camerman and A. Camerman J. Amer. Chem. SOC. 1970,92 2523. ''I J. Konnert J. W. Gibson I. L. Karle M. N. Khattak and S. Y. Wang Nature 1970 227 953. 14' N. J. Leonard K. Golankiewicz R. S. McCredie S. M. Johnson and I. C. Paul J. Amer. Chem. SOC. 1969 91 5855. P. Richter and E. Fahr Angew. Chem. 1969 8 208. 144 P. Richter and E. Fahr Tetrahedron Letters 1970 1921. 145 G. J. Fisher and H. E. Johns Photochem. and Photobiol. 1970 11 429. 502 G. M. Blackburn which are excited to the singlet state. Under these conditions cis-syn and cis-anti dimer formation predominates. 14' The singlet-state formation of the cis-syn dimer from the stacked conformation of 5'-(3'-thymidyly1)thymidine is also much more efficient than the production of the trans-syn-isomer from the unstacked form which suggests that the mechanism of photodimerisation from aggregates is likely to be relevant to the photochemistry ofdT-dT and by extension to DNA.This appears to relegate triplet-state dimerisation to a secondary biological role. However irradiation of DNA above 300nm in the presence of photo- sensitisers produces thymine-thymine dimers' 47,148 with smaller amounts of thymin-ytosine dimer and dihydr~thyrnine,'~' and reflects the close matching of triplet energies for thymine and the ketone photosensitisers.' 50 The mech- anism of the triplet process has been studied in organic solvents' 'and probably proceeds through an adduct of a triplet pyrimidine and an unexcited molecule possibly of diradical structure (15) which normally dissociates to give ground- state pyrimidines but less frequently cyclises.The low efficiency of the latter 0 0 (15) process explains the low quantum yields found for the photosensitised dimerisa- tion. It is noteworthy that thymine-containing dimers are formed during sun- light-irradiation of human cells in uitro.' s' The structure of the thymine-thymine adduct (16) which is obtained'53 on irradiation of thymine at -196 "C has been confirmed by X-ray analy~is."~ A similar adduct (17) joins thymine and uracil'55 and may be formed from the intermediate oxetane (18). This adduct is unstable and dehydrates to 4-(6-thyminyl)pyrimidin-2-one (19) which comprises about one-sixth of the total thymine-derived photoproducts in the DNA of M.radiodurans.' 56 While there is no evidence for the formation ofa thymine-thymine adduct in irradiated DNA (19)can be formed by the deamination of a cytosine-thymine adduct'57 although 146 R.Lisewski and K. L. Wierzchowski Chem. Comm. 1969 348. 14' R. Ben-Ishai E. Ben-Hur and Y. Hornfeld Israel J. Chem. 1968 6 769. M. L. Merstrich A. A. Lamola and E. Gabbay Photochem. and Photobiol. 1970 11 169. 149 A. A. Lamola Photochem. and Photobiol. 1969 9 291. B. H. Jennings S.-C. Pastra and J. L. Wellington Photochem. and Photobiol. 1970 11 215. 151 P. J. Wagner and D. J. Bucheck J. Amer. Chem. SOC.,1970 92 181. J. E. Trosko D. Krause and M. Isoun Nature 1970 228 358. IS3 R. 0. Rahn Photochem.and Photobiol. 1969 10 131. 154 I. L. Karle Acta Cryst. 1969 B25,2119. 155 D. F. Rhoades and S. Y. Wang Biochemistry 1970 9 4416. 156 A. J. Varghese and R. S. Day Photochem. and Photobiol. 1970 11 51 1. 15' A. J. Varghese and M. H. Patrick Nature 1969 223 299. Nucleic Acids 503 0 0 0 (18; R = H) (16; R = Me) (19; R = H) (17; R = H) H H (20) the major thymine photo-product of frozen DNA is claimed to be S(7-thyminyl)- 5,6-dihydrothyminels8 (20) which is also obtained via irradiation of thymidine in ice.lS9 Various other molecules bind photochemically to purines and pyrimidines both in model systems and in DNA. Cysteine forms a mixed photoproduct with thymine linked from sulphur to C(5),l6' and reaction of this amino-acid with uracil simultaneously produces dihydrouracil and 6-(S-cysteinyl)-5,6-dihydro-uracil.16' Both U.V.and gamma radiation convert purine nucleosides in the presence of propan-2-01 into 8-(2-hydroxyprop-2-y1)-purines' 62 and similar products are produced from DNA.'63 The carcinogenic 3,4-benzpyrene gives an adduct with thymine on irradiation at 369 nm in aqueous acetone which is formulated as (21) or an isomeric cyclobutane add~ct'~~ and which appears to be identical with the photoproduct derived from 3,4-benzpyrene and DNA.165 Several furocoumarins such as psoralen xanthotoxin and bergapten which are skin photosensitising agents are also covalently linked to DNA on irradiation in ~itro.'~~.'~'The cyclobutane adducts have thymine residues of the DNA bound either to the coumarin ring (22) or to the furan ring (23)'66 and the forma- tion of photoadducts of this type in uivo may well be responsible for epidermal cell damage.'68 5n A.J. Varghese Biochem. Biophys. Res. Comm. 1970 39 543. A. J. Varghese Biochemistry 1970 9 478 1. 16* K. C. Smith Biochem. Biophys. Res. Comm. 1970 39 1011. 16' T. Jellinck and R. B. Johns Photochem. and Photobiol. 1970 11 349. 16' H. Steinmaus I. Rosenthal and D. Elad J. Amer. Chem. Soc. 1969 91 4921. lti3 H. Steinmaus D. Elad and R. Ben-Ishai Biochem. Biophys. Res. Comm. 1970 40 1021. C. Antonello F. Carlassare and L. Musajo Gazetta chim. Ital. 1968 98 30. 16' C. Antonello and F. Carlassare Z. Naturforsch. 1970 B 1269 L. Musajo and G. Rodighiero Photochem.and Photobiol. 1970 11 27. D. M. Kramer and M. A. Pathak Photochem. and Photobiol. 1970 12 333. 16' M. A. Pathak and D. M. Kramer Biochim. Biophys. Acra 1969 195 197. G. M. Blackburn 0 (23) Photodimers appear to have regained attention as the prime cause of bio- logical U.V. irradiation damage. In bacteriophage T4,thymine dimers are equally capable of producing deletion or transition mutations as of killing the phage. 169 Dimers in phage A are repaired at low levels by recombination processes-whereby two damaged DNA duplexes swap short homologous segments to give one undamaged duplex. At high levels of dimerisation repair involves the excision of dimers by en~yrnes'~' which are provided by the host bacteri~m.'~' Bacterial thymine dimers very efficiently arrest the transcription of DNA'72 and the extent of recovery of messenger RNA synthesis corresponds well to the decrease in thymine dimers remaining in the DNA.'73 In Micrococcus lyso-deikticus an endonuclease operates on the irradiated DNA to create single- strand nicks by hydrolysis of phosphodiester bonds which enables an exonuclease to cut out thymine dimer~.'~~ Kornberg's DNA polymerase from E.coli also releases thymine dimers from nicked irradiated p~lydA-polpdT.~~ It is by no means clear what is the precise role of this famous enzyme because a mutant of E. coIi p3478 devoid of this enzyme'75 still multiplies normally can excise pyrimidine dimers,' 76 and is unusually sensitive to radiation damage. Witkin has observed that the rate of u.v.-induced mutations in p3478 is not different from that in normal E.coli which shows that DNA polymerase is not a component of the error-prone repair systems which fail to detect lesions causing lh9 M. L. Meistrich and R. G. Shulman J. Mol. Biol. 1969 46 157. I7O M. Radman L. Cordone D. Krsmanovic-Simie and M. Errera J. Mol. Biol. 1970 49 203. J. M. Boyle and R. B. Setlow J. Mol. Biol. 1970 51 131. H. Michalke and H. Bremer J. Mol. Biol. 1969 41 1. I" S. Yonei F. Tokunaga and K. Nozu Photochem. and Photobiol. 1969 9 537. Y. Takagi M. Sekiguchi S. Okupo H. Nakayama K. Shirrida S. Yasuda T. Nishi-moto and H. Yoshihara Cold Spring Harbor Symp. Quant. Biol. 1968 33 219. 17' P. de Lucia and J. Cairns Nature 1969 224 1164. 17' J.M. Boyle. M. C. Patterson and R. B. Setlow Nature 1970 226 708. Nucleic Acids 505 these mutations.28 Kornberg’s enzyme may thus be responsible for that part of the ‘cut-and-patch’ repair system which operates on the DNA of invading bacteriophage 4x174 and A inside the host cell.29 Our own repair mechanisms for U.V. damage are of vital importance but have only received attention in cases where they are defective. The rare hereditary disease Xeroderma pigmentosum is associated with a diminished tolerance to sunlight and the development of skin tumours :people with this disease cannot respond to U.V. radiation with the normal repair of damaged DNA’77 because of a deficiency in their capacity to excise thymine dimers from the DNA.’78 A second type of molecular defect in X.pigmentosum cases involves a later stage in the repair-possibly the ‘patching’ which follows the ‘cu~.”’~ y-Radiolysis of thymine produces 5-methyl-5-hydroxyhydantionas well as 5,6-dihydro~y-5,6-dihydrothymine’~~ and pulse radiolysis techniques have re- vealed some of the details of the interaction of hydroxyl radicals with DNA and its component^.'^'-'^^ The nature of the reaction between chemically-generated singlet oxygen and nucleosides or nucleotides implies that it could be the active principle in photodynamic processes involving nucleic acid components. 84 5 Pairing and Stacking Conformations Circular dichroism has been the vehicle on which major developments in con- formational studies in this field have advanced and empirical theories have been refined to account for much of the observed behaviour of nucleosides”’ and polynucleotides.’ Nevertheless the technique necessarily focuses attention on the behaviour of the bases while other techniques bring other conformational problems into perspective.An investigation of the properties of poly 2’-O-methyladenylic acid and poly 2’-O-methylcytidylic acid shows that they form helices with polyU’86 and p~lyl’~~ respectively in very much the same way as do polyA and polyC. This discredits the idea that polyribonucleotides differ from their 2’-deoxy counter- parts by virtue of a direct interaction of the 2’-hydroxy-group with an adjacent phosphate possibly through a hydrogen bond and instead favours the idea that a conformational change of the ribofuranose ring is responsible.’88 Given sufficient resolution conformations can be examined by n.m.r.for all parts of the nucleotide unit. The ‘H n.m.r. spectra of dinucleotides indicate that temperature-induced conformational changes involve rotation around J. H. Epstein and K. Fukuyama Science 1970 168 1477. ”’ J. E. Cleaver and J. E. Trosko Photochem. and Photobiol. 1970 11 547. 179 E. C. Jung Nature 1970 228 358. R. Teoule and J. Cadet Compt. rend. 1969 2680 2501. G. Scholes R. L. Wilson and M. Ebert Chem. Comm. 1969 17. ln2L. S. Myers and L. M. Theard J. Amer. Chem. SOC.,1970 92 2868. L. S. Myers A. Warmick M. L. Hollis J. D. Zimbrick L. M. Theard and F. C. Peterson J. Amer. Chem. SOC. 1970 92 2871. F. R.Hallett B. P. Hallett and W. Snipes Biophysical J. 1970 10 305. InsW. C. Johnson and I. Tinoco Biopolymers 1969 7 727. A. M. Bobst F. Rottman and P.A. Cerutti J. Mot. Biol. 1969 46 221. B. Zmudzka C. Janion and D. Shugar Biochem. Biophys. Res. Comm. 1969,37,895. A. M. Bobst P. A. Cerutti and F. Rottman J. Amer. Chem. SOC.,1969 91 1246. G. M. Blackburn phosphate ester bonds189 and also supports the idea that base-stacking in dinucleotides stabilises the 3‘-endo- over the 2’-endo-conformation for ribose. ‘90 Nearly 80 X-ray structures of nucleosides nucleotides coenzymes poly- nucleotides and nucleic acids have been analysed in terms of all the conforma- tional angles in the sugar phosphate and glycosidic bond^.'^^,'^^ Surprisingly this shows that conformational angles in the monomers are confined within narrow ranges and demonstrates that the torsion angle of the glycosidic bond (24; x) is markedly influenced by the mode of puckering of the furanose ring.Moreover the range of conformations for the six bonds of the polymer backbone (24; o,4 $ $’ +’,and 0’) is equally restricted and virtually imposes stacking on the bases. As a result the observed preferred conformation of a single nucleotide is about the same as that found for the same unit incorporated into the nucleic acid polymer. Similar conclusions have been drawn from a shorter survey of phos- phodiester conformations. ’93 These conclusions have received independent support from an investigation of the conformation of polyU the classically ‘disordered’ polymer.It appears to exist as a highly-extended stiff random coil a state also observed for unstacked polyA whose properties suggest that all the bonds in the sugar-phosphate back- bone of the RNA exhibit highly restricted r0tati0n.l~~ Several reviews have described the physical characteristics of single- double- and triple-stranded nucleic acids,‘ 95 the specificity of hybridisation,’ 96 the mechanism of unwinding of DNA,19’ and mathematical analysis of the nature of co-operative conformational transitions’ 98 which includes a specific treatment P. 0.P. Ts’o N. S. Kondo M. P. Scheweizer and D. P. Hollis Biochemistry 1969 8 997. 19* B. W. Bangerter and S. I. Chan J. Amer. Chem. SOC.,1969 91 3910. 191 S. Arnott and D. W. L. Hukins Nature 1969 224 886.92 M. Sundaralingam Biopolymers 1969 7 82 I. 193 E. Shefter M. Barlow R. A. Sparks and K. N. Trueblood Acta Cryst. 1969 B25 895. 194 L. D. Inners and G. A. Felsenfeld J. Mol. Biol. 1970 50 373. 95 R. Steiner and D. B. S. Millar ‘Biological Polyelectrolytes’ ed. A. Veis Marcel Dekker New York 1970. p. 65. 19’ B. J. McCarthy and R. B. Church Ann. Ret.. Biochem. 1970.39. 131. 19’ D. M. Crothers Accounts Chem. Res. 1969 2 225. 198 J. Engel and G. Schwarz Angew. Chem. Internat. Edn. 1970 9 389. Nucleic Acids of the transition from helix to coil forms of nucleic acids. The phenomenon of co-operativity is displayed in the sharpness of the transition between alternative conformers and in its dependence on the chain length of the linear polymer.In general segments of such co-operative systems favour the same conforma- tional unit state as that of their neighbours because of intra-strand inter-act ions. Eigen chose to examine the nature of the initiation process for helix formation by analysis of oligoadenylates with chains shorter than the co-operative length.”’ Whereas oligomers of complementary purines and pyrimidines form only triple- stranded helices such as polyA.2p0lyU,~~~ polyA forms a double-stranded complex at slightly acidic pH. He interprets his data by means of the simplest co-operative model which assumes that there is one value for the association constant for the first step in base-pairing PS and a second value S for all sub-sequent steps in chain growth.If p << 1 then short oligonucleotides will display ‘all-or-none’ transition between random and helical conformations. Eigen’s results show that the enthalpy factor of the first base-pairing is close to zero but subsequent pairing adjacent to an existing pair is stabilized by about -12 kcal mol-I and Craig reaches a similar conclusion from experiments on oligouridylic acid dimers.201 Developing from the polyA studies Eigen has investigated kinetic and equilibrium relationships between polyA and polyU202 which provide some experimental basis for his theory of 6 RNA The discovery of interferon,204 a protein manufactured in animal cells which offers protection against a wide range of DNA and RNA viruses was followed ten years later by the observation that its activity was stimulated by double-stranded RNA.’05 One of the most active RNAs is the synthetic polyI.polyC.206 This RNA has been used in animals against influenza vaccinia and polio-like viruses rabies and trachoma2’ with favourable results.Its action against tumours is probably a superposition of three effects :a direct stimulation of interferon a direct and selective chemotherapeutic impact of poly 1-polyC on the biosynthesis of tumour-inhibiting macromolecules and an enhancement of immunological rejection mechanism^.^^' Emphasis should be placed on the first of these since the pretreatment of monkey cells with polyI-polyC IY9M. Eigen and D. Porschke J. Mol. Biol. 1970 53 123. zoo P. M. Pitha and P. 0. P. Ts’o Biochemistry 1969 8 5206.‘01 M. E. Craig Fed. Proc. 1969 28 No.2 p. 531. ’OZ D. Porshke Dissertation 1969 Universitat Carolo-Wilhelmina Braunschweig. ‘03 M. Eigen As yet only presented as conference reports; cf. Nachrichten aus Chemie und Technik 1970 18 439; Chemistry and Industry 1970 1166; Nature 1971 229 85. ‘04 A. Isaacs and J. Lindemann Proc. Roy. SOC. 1957 B147,258. ’05 A. K. Field A. A. Tytell G. P. Lampson and M. R. Hilleman Proc. Nut. Acad. Sci. U.S.A. 1967 58 1004. ’06 G. P. Lampson A. A. Tytell A. K. Field N. M. Nemes and M. R. Hilleman Proc. Nat. Acad. Sci. U.S.A. 1967 58 782 et seq. ’07 H. B. Levy R. Asofsky F. Riley A. Garapin H. Cantor and R. Adamson Ann. N. Y. Acad. Sci. 1970 173 640. 508 G. M. Blackburn is only effective against virus infection if the cells are capable of producing interferon.2o Merigan has made a careful study of the efficiency of different RNAs as in- ducers of interferon or virus-resistance from which a correlation emerges between the activity of the polymer and its thermal stability.If the polymer 'melts' at 60 "C or a higher temperature it is very active irrespective of its base composition. Polymers with lower thermal stability even polyA.polyU of T 57-5"C are significantly less effective. Since the nucleic acid must be double stranded to induce interferon and the thiophosphate analogue 2poly(Ap"Up") is both a good activator for interferon and has a high level of resistance to ribonuclease it could well be that the requirement for a thermally-stable RNA is also linked to re- sistance to RN~s~.~" Mammalian DNA viruses may also stimulate interferon in the same way because double-stranded RNA is found in virus-infected chicken cells and is probably copied from the viral DNA.210 7 Transfer RNA The number of known primary structures of tRNAs has risen well above the thirteen described in the 1968 Report.'32 Structures have been described for the leucyl,2' phenylalanyl,2'2 tryptophanyl,2'3 and valyl ,214,215 tRNAs from E.coli tRNA"' 216 and tRNATyr217 from a Torulopsis yeast tRNAASp218 from brewer's yeast and several more tyrosine suppressor ~RNAs.~' The reproducibility of aII the known tRNAs in a clover-leaf secondary structure must now make the odds against its being an artefact somewhere in the region of Avogadro's number to one ! Generalized secondary structures incorporating features common to the majority of tRNA sequences have experienced successive relaxation of their constraints as further sequences have been p~blished,'~~*~~~*~~' The model presented here (Figure 4)will no doubt suffer the same fate in due course.Certain aspects of the general structure appear to be reliable. Three of the four major helical stems are of constant length while stem b may have three or four base-pairs. Non-complementation of bases in the stems is rare only occasionally exceeding one per molecule and is observed most frequently at the loci indicated in stem a. Such mispairing is most commonly of the G.U combination also apparent in other RNA helices (p.513) which presumably causes little distortion '08 T.W. Schafer and R. Z. Lockart Nature 1970,226,449. '09 E. De Clercq F. Eckstein and T. C. Merigan Ann. N.Y. Acad. Sci. 1970 173 444. 210 C. Colby and P. H. Duesberg Nature 1969 222 940. 211 S. K. Dube K. A. Marcker and A. Ydelevich F.E.B.S. Letters 1970 9 168. '12 B. G. Barrell and F. Sanger F.E.B.S. Letters 1969 3 275. 'I3 D. Hirsh Nature 1969 228 56. 'I4 M. Yaniv and B. G. Barrell Nature 1969 222 278. z15 F. Harada F. Kimura and S. Nishimura Biochim. Biophys. Acta 1969 195 590. 216 S. Takemura M. Murakami and M. Miyazaki J. Biochem (Japan) 1969 65 489. 217 S. Hashimoto M. Miyazaki and S. Takemura J. Biochem. (Japan) 1969 65 659. 'I8 G. Dirheimer L. Kisselev and T. Venkstern F.E.B.S. Letters 1970 11 73.'I9 J. D. Smith L. Barnett S. Brenner and R. L. Russell J. Mol. Biol.,1970 54 1. 220 G. R. Philipps Nature 1969 223 374. 221 M. Levitt Nature 1969 224 759. Nucleic Acids 509 I 5 5’ R ‘Anticodon Loop’ Figure 4 General secondary structure for tRNA. Restricted base positions are indicated by the appropriate letter,3 others by points. The stems a b c and e usually contain bases in complementary pairs. 8indicates loci of non-complementation. Loop I may contain 1 2 or 3 of the loci in parenthesis. Loop 111 varies between 1 and 13 bases in all of the helix. Isolated examples of U.U13’and G.AZz2have also been recorded the latter also detected in one mutant tyrosine tRNAYZI9 is necessarily a helix- distorting element. The variability in size and composition of loop I contrasts markedly with the constancy of loop IVYand yet loop I is the site where enzymes make many secondary modifications hydrogenating or isomerising U and methylating G on the ribose 2’-hydroxy-group.However the sequence -A,,-G(A) ,-Y 6-appears to be common to all sequences except Holley’s tRNAIAla which contains -A -G -D -.I31 16 17 18 Single crystals which contain up to seven different tRNA species furnish X-ray diffraction patterns suggestive of a marked similarity of gross structure for all tRNA species,223 but the breakthrough in tertiary structure by X-ray analysis has not yet materialised. The Patterson projections now available fit a model with a long double helixzz4 which accords with an estimate of the separation of the 222 B.S. Dudock G. Katz E. K. Taylor and R. W. Holley Proc. Nat. Acad. Sci. U.S.A. 1969 62 941. 223 R. D. Blake J. R. Fresco and R. Langridge Nature 1970 225 32. 224 M. Labanauskas P. G. Connors J. D. Young R. M. Beck J. W. Arderegg and W. W. Beeman Science 1969 166 1530. G. M. Blackburn Amino-acid Ar.m C I OB Di hydro -U TWC Loop Loop Anticodon Loop Figure 5 Tertiary structure oftRNA (after Levitt’”). Not all base-pairings are repre- sented anticodon and the 3‘-terminus based on fluorescent quenching of at least 40 A.’” Consequently the problem of tertiary structure has lain in the hands of the model builders. They have been assisted by several studies of those locations in the tRNAs which are susceptible to chemical modification.Methoxyamine,226 keth~xal,~~’ and monoperphthalic acid,228 a~rylonitrile,~~~ a water-soluble ~arbodi-imide’~’are all able to attack and modify bases in loops I 11 and I11 while loop IV appears to be relatively immune. That suggests loop IV is ‘buried’ in the tertiary structure. Ribonuclease can show similar selectivity though there are examples of RNase TI operating on a bond in loop IV.2319232 An entirely different approach uses the isolated sensitivity of 4-thiouridine in the %position to 335 nm U.V. radiation causing it to bond to the cytidine in position-13.233 Several model structures have been proposed to account for some or all of these data and for the known physical properties of ~RNAs.’~~ None is quite as ingenious as that of who has planned the structure to maximise both base-pairing and stacking.The result (Figure 5)is surprisingly compact though 2L5 K. Beardsley and C. R. Cantor Proc. Nat. Acad. Sci. U.S.A. 1970 65 39. 226 T. I. Jilyaeva and L. L. Kisselev F.E.B.S. Letters 1970 10 229. ”’ M. Litt Biochemistry 1969 8 3249. ”’ F. Cramer H. Doepner F. van de Haar E. Schlimme and H. Seidel Proc. Nat. Acad. Sci. U.S.A. 1968 61 1384. 229 M. Yoshida and J. Ukita Biochim. Biophys. Acta 1966 123 214. ”O S. W. Bronstoff and V. M. Ingram Biochemistry 1970 9 2372. 23L N. Imura G. B. Weis and R. W. Chambers Nature 1969 222 1147. 232 A. D. Mirzabekov D. Lastity E. S. Levina and A. A. Baev Nature New Biol. 1971 229 21. 233 M. Yaniv A.Farve and B. G. Barrell Nature 1969 223 1331. 234 For a review see reference 221. Nucleic Acids 51 1 somewhat contorted in the T-Y-C region of loop IV. The elongated molecule has a radius of gyration of 23 A which is close to that determined by physical measurement. It places the anticodon and the amino-acyl acceptor sites at opposite ends by stacking stem a on stem e and stem b on stem c in such fashion that residues 8 and 14 can base-pair and that residue 15 always a purine can pair with the base which precedes stem e always the complementary pyrimidine. In addition the T-Y-C sequence of loop IV is shielded by its interaction with loop I though leaving parts of the latter accessible for chemical reaction. Each tRNA can be esterified by the appropriate amino-acid on its terminal adenosine 3’-hydroxy-group under the influence of a specific synthetase.Attempted identifications of the specific binding site on various tRNAs for these enzymes are sufficiently conflicting as to suggest that the site is different in location and structure in different species or that many of the attempted identifications are valueless. Suggestions that most of the tRNA molecule can be modified or even removed without impairing aminoacyl acceptan~e,~~~?~~~ providing that the a stem and the C-C-A terminus are intact must be treated with caution. Much the most elegant study has used mutant tyrosine tRNAs219 These all have the anticodon CUA corresponding to the nonsense codon UAG but are charged with tyrosine by the synthetase.Thus their properties can be compared with those of the original su& tyrosine suppressor tRNA of known sequence.132 Protein synthesis is greatly diminished in mutants where a G-C base-pair has been changed into an AC or a G-A base-pair in the su; tRNATy‘ but in two cases one each in stems a and b normal activity is restored by a second mutation which completes the change of GC into A.U. A single mutation of type G-C+G.U does not impair activity of the tRNA. This shows that full helicity is required in stem a but that recognition of the tRNA by the synthetase is not dependent on the base composition of that stem. Smith has also shown that a GC -+AC change in stem c impairs binding of the tRNA to the enzyme while a G +A change in loop I interferes with a later stage of protein ~ynthesis.’~’ Evidence is accumulating that both tRNA and 5s ribosomal RNA are derived from substantially larger precursors.The preliminary identification of RNA species which have some 3540nucleotides more than mature tRNATy‘ and with different 3’-and 5’-termini has also shown that the molecules are short-lived in vivo. Fingerprint techniques have identified the components of at least one complete tRNATy‘ sequence in the precursors but with unmodified A G,and U residues.238 Ribosomal RNAs may also be derived from larger precursor^.^^^-'^^ 235 U. Lagerkvist and L. Rymo J. Biol. Chem. 1970 245 435. 236 References cited in reference 232.. 237 J. N. Abelson M. L. Gefter L. Barnett A. Landy R. Russell and J.D. Smith J. Mol. Biol. 1970 47 15. 238 S. Altman Nature New Biol. 1971 229 19. 239 M. Bleyman M. Konde N. Hecht and C. Woese J. Bacteriol. 1969 99 535. 240 W. F. Doolittle and N. R. Pace Nature 1970 228 125. 241 M. Hughes and F. C. Kafatos Biochem. Biophys. Res. Comm. 1970 39 1108. 242 M. Adesnik and C. Levinthal J. Mol. Biol. 1969 46,281. 243 B. R. Jordan J. Feunteun and R. Monier J. Mol. Biol. 1970 50 605. 512 G. M. Blackburn 8 Ribosomal RNA The sequence has been determined for three fragments of 16s rRNA together containing 284 residues-some 18 per cent of the total molecule. It is possible to arrange these segments in conformations of high helical content with multiple stem-loop features similar to those favoured for tRNAs partly supported by the patterns of partial enzymic digestion.244 Doty has developed one technique which may help to verify such structures.Equilibrium dialysis is used to determine the strength of binding of synthetic tri- and tetra-nucleotides to RNA molecules which presumably select for com- plementary single-stranded regions of the RNA molecule under test. This approach has been monitored on tRNAF" by short oligomers complementary to parts of loop 11 and then used to locate four principal binding sites in E. coIi 5s RNA.245 The results correlate well with one of three structures proposed by consideration of base-pairing only. The secondary structure proposed for 5s RNA from KB cells has been revised.246 Whether or not such proposed structures have any relation to reality ribosomal RNAs definitely have specific conformations in the assembled ribosome and both partial enzymic digestion247 and dye intercalation248 studies are beginning to probe the nature of the intact ribosome.Its structure may be just round the corner.249 9 Viral RNA The primary sequences of single-stranded RNA viruses are not merely fascinating in themselves they are the nominal objective of a multiple-target research vehicle whose spin-off provides confirmation of the genetic code in uiuo guides to the nature of initiation sequences for protein synthesis general features of RNA secondary structure and the possible use of the latter in control processes. The prime targets have been the sequences of the single-stranded RNA of R17 and Qp the former virus specifying three proteins and the latter four proteins in viva The primary sequence of bases in a 57-nucleotide fragment of R17 can be translated into protein in three ways depending on the phase of grouping the bases in triplets.One of these readings corresponds to an octadecapeptide (Figure 6)which has the amino-acid sequence of residues 82-99 of the R17 coat protein' and incidentally provides in vivo confirmation for 17 of the 64 codons. This RNA fragment can be presented as a looped hairpin (Figure 6) containing 20 complementary base-pairs and only one purine-purine interaction. A second fragment 44 bases long (Figure 7a) contains codons for the C-terminal hepta- peptide of the coat protein followed by a double 'full stop'-the two nonsense codons UAA and UAG.250 Seven bases at the 3'-end of this sequence overlap the 244 C.Ehresmann P. Fellner and J. P. Ebel Nature 1970 227 1321. 245 J. B. Lewis and P. Doty Nature 1970 225 510. 246 B. G. Forget and S. M. Weissman J. Biol. Chem. 1969 244 3148. 247 K. A. Hartman J. Amaya and E. M. Schachter Science 1970 170 171. 248 A. Bollen A. Herzog A. Favre J. Thibault and F. Gros F.E.B.S. Letters 1970 11 49. 249 C. G. Kurland Science 1970 169 1171. 250 J. L. Nichols Nature 1970 225 147. Nucleic Acids 4- r& a1 au 01 3 -I a. u r& 5 14 G.M. Blackburn 5'-end of a 35-nucleotide fragment (Figure 76) which contains the AUG codon signalling the initiation of protein synthesis immediately followed by codons for the N-terminal pentapeptide of the synthetase protein.251 Other oligoribo- nucleotide sequences have been analysed which complete nearly half the coat protein gene and confirm more than half the code assignments as well as demon- strating the extent to which its degeneracy has been put to use in uioa2' The 74 nucleotides of the 5'-end of R17 have been but do not code for any R17 protein.They do however form two hairpin loops each of which shows considerable homology of sequence with similar loops located in the first 130 residues of the 5'-terminus of phage QD,20 which likewise appears to code for no protein within the first 200 nucleotides. Available sequence data for R17 can be used to compile a biochemical map (Figure 8) which unequivocally e~tablishes~~ a new order for the three-protein 1 234567 8 Known Sequences PPPG4 A Protein ).1 Coat H Synthetase +OH I 1 1060 2060 3060 3560 Residues Figure 8 Biochemical map of R17 (to scale) genes 5'-A protein<oat protein-synthetase-3'.A similar revision has been made for the related phage M12 using the synchronous synthesis technique.253 The biochemical map can be enlarged to show secondary structure (Figure 9) in 5'GA.....AUG._.__ JL n n n .. . . . . . . -.. . ... ... . .. LAOH31 uhG ___..____.__. Figure 9 Conformational map of R17(not to scale) (Known sequences -; unknown sequences + . . .) the eight regions of known sequence though this is but 12 per cent of the total RNA.239254The fact that nearly half the coat protein gene can be accommodated in five hairpin loops may signal the economy with which the virus packs its genome into the protein envelope.If such double-stranded highly-complementary hairpin loops prove to be general features of viral RNAs it follows that the distribution of amino-acids in viral proteins is thereby restricted. For instance if the codons for a tripeptide His-Met-Trp sequence occur in a non-terminal hairpin the same hairpin is likely to contain the anticodons CCA-CAU-6UG. This would require the presence of one of three peptide sequences Pro-His-M,;; His-#E,-Cys or X-Thr-2; within about 15 residues from the conjugate tripeptide. Even though lS1 J. Hindley and B. Staples Nature 1969 224 964. 252 J. M. Adams and S.Cory Nature 1970 227 570. 253 R. N. H. Koningo R. Ward B. Francke and P. H. Hofschneider Nature 1970,226 604. 254 A Special Correspondent Nafure 1970 226 1093. Nucleic Acids 515 this restriction can obviously be relaxed by mispairing in the hairpins it may still call into play the full degeneracy of the code to overcome the consequent limita- tions on the tertiary structure of viral proteins. It appears more than likely that the gross structure of the RNA at the point of initiation of protein synthesis is involved in the discrimination which produces very disparate rates of synthesis for the A coat and synthetase proteins (about 7 :20 :1 respectively). For bacteriophage f2 disorganization of the secondary structure by mild treatment of the RNA with formaldehyde produces a 3-fold decrease in coat protein synthesis but a larger increase in the yield of synthetase and maturation After its infection by phage QP the bacterial cell sets about the synthesis of a (-) strand antiparallel to the infective QP (+) strand.The sequence of the first 52 residues of the 5’-end of the (-) strand proves to be precisely complementary to the equivalent portion of the 3’-end of the (+) strand.256 While this result caused no surprises another aspect of Qp had posed a real problem for some time the four virus-specific proteins were ‘too big’ for the RNA content of the virus! The A, A, coat and replicase proteins contain 1500 amino-acid residues between them while the RNA is but 3500 nucleotides and its coding capacity is only about 1150 arnino-acid~.~~~ This paradox has been resolved by the dis- covery that only one of the four proteins in Qp replicase is translated from the viral RNA while the other three proteins are manufactured by the E.coli host cell before it is infected with the The reproductive pattern of these bacterial viruses can be described @A -+ Protein and presents no threat to the Central Dogma (p. 489). Not so the behaviour of single-stranded RNA tumour viruses Rous sarcoma virus and the like the discovery of an RNA-dependent DNA polymerase by Baltimore4andTemin5 threatened to upend the dogma which,redefined by Crick,* now accepts the reverse transcription of RNA into DNA as a special event. This event common to a wide variety of avian and mammalian RNA viruses involves the formation of a hybrid duplex which has one strand of RNA and its complement in DNA from at least part of the viral RNA.258,259The hybrid is then converted into a DNA-DNA duplex by a DNA-dependent DNA poly- merase.260-262 A s much the best template for this enzyme is p~lydC.polyrG,~~~ 255 H.F. Lodish J. Mof. Biof. 1970 50 689. 256 H. M. Goodman M. A. Billeter J. Hindley and C. Weissmann Proc. Nat. Acad. Sci. U.S.A. 1970 67 921. 25’ M. Kondo R. Gallerani and C. Weissmann Nature 1970 228 525. ’’’S. Spiegelman A. Burny M. R. Das J. Keydar J. Schlom M. TrhvniEek and K. Watson Nature 1970 227 563. 259 M. Rokutanda. H. Rokutanda M. Green K. Fujinaga R. K. Ray and C. Gurgo. Nature 1970 227 1026. 260 S.Spiegelman A. Burny M. R. Das J. Keydar J. Schlom M. TrBvniEek and K. Watson Nature 1970 227 1029. 261 S. Mizutani D. Boettiger and H. M. Temin Nature 1970 228 424. 2h2 J. Riman and G. S. Beaudreau Nature 1970 228 427. S. Spiegeiman A. Burny M. R. Das J. Keydar J. Schlom M. TravniCek and K. Watson Nature 1970 228 430. 516 G. M. Blackburn Spiegelman suggests that synthetic duplexes might be used for monitoring this enzyme in virus-infected cells. Such an approach could have far-reaching consequences in view of the demonstration that cells from human acute-leukaemia patients show RNA-dependent DNA polymerase This could be a site not only for the development of an assay for human cancer viruses but also for a new chemotherapy. 10 Protein Biosynthesis The total machinery for protein biosynthesis requires well over a hundred species of macromolecules -tRNAs charging enzymes ribosomal components etc.Recent attention has focused on the control features of synthesis which involved three types of protein factors in bacteria. mRNA INITIATION fMet ATION '-f- ,GDP* 42 pi*! ELONGATlON 5' 5' .GTP s2 1 GDP GiP+ AA -t RNA Figure 10 Initiation elongation and termination steps in protein biosynthesis 264 R.C. Gallo S. S. Yang and R.C. Ting Nature 1970 228 927. Nucleic A cids 517 The first type controls the start of synthesis. The factors F ,F, and F are all involved with bringing the messenger RNA the ribosomal particles and the formylmethionyl tRNA2“ onto the correct initiation site of the messenger RNA (Figure 10; 1and 2) although it is not certain whether they regulate the frequency of translation of different messages on the same RNA ~trand.’~~-’~’ Th e formation of the initiation complex is linked to the hydrolysis of one mole of GTP (Figure 10; 2) and only involves the smaller ribosomal particle-the 30s unit.268 Once this initiation complex has combined with the 50s ribosomal particle (Figure 10; 3) the system has the same capacity to join the cycle of elongation reactions (Figure 10; 4-6) as a peptidyl-tRNA complex.This cycle is under the control of three different factors S ,S, and S .269,270 The S factor promotes the formation of a complex between the incoming aminoacyl-tRNA GTP and the S factor which then adds to the peptidyl- tRNA mRNA ribosome complex (Figure 10; 4).This aggregate contains on the 50s particle the enzyme catalysing peptide-bond formation which operates with the transfer of the peptidyl group to the amino-function of the aminoacyl-tRNA. The concomitant hydrolysis of the GTP releases phosphate and gives an adduct of the S3 factor with GDP (Figure 10; 5). The final part of the chain-elongation process uses the S factor energised by another mole of GTP to expel the spent tRNA and translocate the newly-generated peptidyl-tRNA (Pep’) from the aminoacyl to the peptidyl site on the 50s particle (Figure 10; 6). This completes the elongation cycle and gives a peptidyl-tRNA complex with one more amino- acid which either rejoins the elongation cycle (Figure 10 ;4) or enters the termina- tion process (Figure 10; 7).Rather surprisingly this cycle also catalyses the formation of a carboxylic ester if one or-aminoacyl-tRNA is replaced by its deamination product an cc-hydr~xyacyl-tRNA.~’ The completion of chain synthesis follows the recognition of one of three termination signals UAA UAG or UGA in the aminoacyl site. Two protein termination factors R and R ,respond to these signals by hydrolysing the ester bond holding the completed peptide onto the final tRNA (Figure 10; 7); R recognises UAA and UAG while R2 responds to UAA and UGA.272 It has been suggested that UAA familiarly called OCHRE, is the normal chain terminator because it is less easily suppressed than UAG (AMBER) but as has already been noted (p.513) termination of the coat protein in R17 uses both these signals.25o The third nonsense signal UGA (OPAL), is found ahead of and in phase with the 265 M. Revel H. Aviv Y.Groner and Y. Pollack KE.B.S. Letters 1970 9 213 218. 266 H. F. Lodish Nature 1970 226 705. 267 S. Sabol M. A. S. Sillero K. Iwasaki and S. Ochoa Nature 1970 228 1268. J. W. B. Hershey K. Dewey and R. E. Thach Nature 1969 222 944. 2‘ These abbreviations currently denote the elongation factors of B. stearothermophilus. For E. coli the equivalent factors are designated T, G and T,-a nomenclature which is currently more widely recognised. 170 J. Waterson G. Beaud and P. Lengyel Nature 1970 227 34. 271 S. Fahnestock and A. Rich Nature New Biol.1971 229 8. 272 M. R. Capecchi and H. A. Klein Nature 1970 226 1029. 273 T. Suzuki and A. Garen J. Mol. Biol. 1969 45 549. 518 G. M. Blackburn initiation signals for all three proteins in R17,22 which raises the possibility that its task is to ‘clear the register’ before initiation of protein synthesis. Although the RNA which lies between ‘stop’ and ‘start’ signals is not normally translated into protein a base deletion just before the ‘stop’ changes the phase of reading the bases in triplets and allows protein synthesis to continue into the intercistronic region.274 One application of this has been to fuse together two enzymes of S. typhimurium by the introduction of one such frameshift mutation ahead of the terminator signal of the first with a compensating frameshift near the beginning of the second enzyme.The macroprotein produced has both enzymic activities. Although this account of protein synthesis has evolved from studies on different bacterial systems there is now little doubt that the initial steps in protein biosynthesis are substantially the same in higher organisms. Their initiation factors276 also select between two different species277 of tRNAMe‘ neither of which is formylated though bacterial enzymes can formylate that one which binds to initiation fa~tors,~~~,~’~ Met-tRNA Me‘F. The second unformylatable species Met-tRNAMeIM binds to elongation factors.277 Haemoglobin bio-synthesis appears to be initiated by Met-tRNAMetF though the methionyl residue is cleaved from the N-terminus after the nascent protein has reached the eico- sapeptide stage.280-28 The brief existence of messenger RNA is now seen to result from the fact that it is enzymically degraded from the 5’-to the 3’-end the same direction as its synthesis and that the enzyme responsible possibly RNase V bound to part of the ribosome,283 may begin to work on the 5’-end before the 3‘-end of the mRNA has been synthesised!284 The overall picture which emerges is that of a wave- like progression of mRNA synthesis its translation into protein and its degrada- tion which surges along the DNA. This idea is partly supported by the similar velocities of the three reaction^.^^^"*^ If seeing is believing then there is no finer demonstration of the integration of transcription and translation than the electron micrographs of Thomas and his colleagues (Plate 1).This shows286 a horizontal thread of DNA from which RNA threads branch vertically at intervals above and below the DNA with granules of the right size for the RNA polymerase enzyme ”‘ M. M. Rechler and R. G. Martin Nature 1970 226 908. 275 J. Yourno T. Kohno and J. R. Roth Nature 1970 228 820. 27h P. M. Prichard J. M. Gilbert D. A. Shafritz and W. F. Anderson Nature 1970 226 5 11. 277 D. A. Shafritz and W. F. Anderson Nature 1970 227 918. A. E. Smith and K. A. Marcker Nature 1970 226 607. 27y N. K. Gupta N. K. Chatterjee K. K. Bose S. Bhaduri and A. Chung J. Mol. Biol. 1970 54 145. zno A. Yoshida S. Watanabe and J. Morris Proc. Nut. Acad. Sci.U.S.A.,1970.67 1600.2n’ R. Jackson and T. Hunter Nature 1970 227 672. 2n2 D. Housman M. Jacobs-Lorena U. L. RajBhandary and H. F. Lodish Nature 1970 227 913. 283 M. Kuwano D. Schlessinger and D. Apirion Nature 1970 226 514. 284 D. E. Morse R. Mosteller R. F. Baker and C. Yanofsky Narure 1969 223 40. 285aH . M anor D. Goodman and G. S. Stent J. Mol. Biol. 1969 39 1. 285hN. Morikawa and F. Imamoto Nature 1969 223 37. 28h 0.L. Miller B. A. Hamkalo and C. A. Thomas Science 1970 169,392. Plate 1 Polyribosomes attached to an active segment of an E. coli chromosome. The arrow indicates the putative initiation site for RNA synthesis. (Reproduced by permission from Science 1970 169 392) Plate 2 Lac heteroduplex with four single-stranded tails formed by the non-complementary ‘heavy’ strands of the two phages.(Reproduced by permission from Nature 1969 224 768) Plate 3 A single pure lac duplex DNA. (Reproduced by permission from Nature 1969 224 768) Example Strand diagram Chain diagram 0 Ring Lariat 8 Double ring break a Polyring Plate 4 Folded circular structures of DNA tandem sequences. (Reproduced by permission fromJ. Mol. Biol, 1970,51,621) Nucleic Acids 519 at the junctions. Each mRNA has several ribosomes attached along it where protein synthesis operates. The shortest RNA (left side) is near the beginning of the operon and the longest polysome side-chain (right side) must be near its end. Thus the length of the operon can be measured between these points.11DNA Whether you view Beckwith's work as a tour deforce or as the sinister beginning of genetic engineering the isolation of a piece of pure DNA containing only a select set of genes from the lactose operon was elegantly done.'' These DNA genes which are used in E. coli when lactose is the carbon source supplied to the bac- teria can be transferred to bacteriophage. This insertion into the phage DNA can be effected in the same relative location but in opposite orientations for the related phages A and 480 (Figure 11). The DNA of both phages contains one Light Heavy Heavy Light \/ Mix 1 ayzopi & Nuc lease ayzopi IIIIIIIIIIII _____) JrlrlrrlllL a'y'z'o'p'i' 'lac gene' Figure 11 strand which is lighter than the other allowing the two heavy strands to be separated by established means.Though the heavy strand of A is not comple- mentary to the heavy strand of 480 the components of the A and 480 strands derived from the lac insertions are complementary. Only this section will hybridise on annealing the mixture of the heavy strands leaving the remainder of 520 G. M. Blackburn the DNA single-stranded (Plate 2)to be digested away by an appropriate nuclease. This leaves in splendid isolation the double-stranded DNA which contains the major part of the lac operon (Plate 3). For the time being such an approach appears to be restricted to bacterial systems and their viruses but the discovery that mammalian RNA viruses can make DNA which may be incorporated into the host-cell DNAZ6’may raise this limitation.Beckwith’s experiment is one of many which hinges on the hybridisation of complementary strands of DNA or RNA. This technique has been applied to the task of sequencing the single-stranded ends of phage A-one of the ‘easier’ problems in DNA sequencing. DNA polymerase adds radioactive nucleotides to the incomplete 3’-ends of ;1.to complement the bases in the 5’-termini. The added bases can be removed by exonuclease action and analysed to show the sequence of the 1”sticky ends. The first eight residues of each end are entirely composed of C and G.287 When DNA has short multiply-repeated sequences as is the case for portions of the DNA of eucaryotic cells hybridisation can produce curious artefacts.The so-called ‘Satellite’ DNA is of this type and can account for up to one-tenth of the total nuclear DNA of animal cells. The separated strands of satellite DNA reassociate with exceptional rapidity suggesting that they contain tandem repeats of identical sequences each some 200 base-pairs long.288,289 The repeats may be even shorter for guinea-pig satellite DNA with possible sequences290 such as 5‘ C-C-C-T-A-A C-C-C-T-A-A-T-A-A 3‘ ...... or .... . . . . 3‘ -A-T-T P-G-G-A-T-T-A-T-T 5’ The annealing of tandem sequences which have been broken by shearing into short segments has produced some novel DNA configurations (Plate 4) which can be rationalised in terms of the possible variations in strand reassociati~n.~~’ Such considerations apart circular DNA has a vital role in bacteria.It differs from linear DNA because closing the circle makes constant the number of rota- tions of one strand around the other. This topological restriction is especially identified by the appearance of super coil^.'^^ The number of supercoils varies with the pitch of the helix screw and responds to temperature and salt effects292 but is so remarkably constant for unit length of DNAs derived from a variety of sources as to suggest that supercoils result from a standard change in conditions between invim and invitro environments.293 Even so they remain an interesting object for kinetic studies and provide a delicate probe for investigations of physical 287 R. Wu J. Mol. Biol. 1970 51 501.288 K. W. Jones Nature 1970 225 912. 289 W. Hennig and P. M. B. Walker Nature 1970 225 915. 290 E. M. Southern Nature 1970 227. 794. L91 C. A. Thomas B. A. Hamkalo D. N. Misra and C. S. Lee J. Mol. Biol. 1970,51,621. 292 J. C. Wang J. Mol. Biol. 1969 43 25. 293 J. C. Wang J. Mol. Biol. 1969 43 263. Nucleic Acids 521 interplay between DNA and other molecules.294 Such studies will be aided by Vinograd’s latest assay for superhelix den~ities.~” Waring has used superhelical changes to study the binding of several drugs antibiotics and other small molecules to closed circular DNA. If these species are able to intercalate (‘slot’) between adjacent base-pairs the resulting elonga- tion and local uncoiling of the helix will cause a change in pitch which is seen as a change in the supercoil conformation.This is likely to become the definitive technique for measuring intercalation and shows that actinomycin behaves as an intercalator while LSD does not.296 Although intercalation of small flat molecules may be important for the action of certain and carcinogen^,^^'.^^^ the physical interaction between DNA and DNA-specific proteins is more important vitally so for those proteins which control the transcription processes. The first of these to be isolated were the proteins for the repression of iand lac operons in bacteria obtained by Pta~hne~~~ and by Gilbert and Muller-Hi11.300 They bind tenaciously and specifically to the DNA of their respective operators with the result that the succeeding genes are ‘turned-off ’ for RNA synthesis.The dissociation constant for this binding is estimated at 5 x10-l4 moll-’ and falls by several orders of magnitude for binding involving a non-specific DNA.301 The binding to polyd(A-T) is sufficiently high to suggest that its alternating sequence may be related to part of that recognised by the repressor protein.302 The measured rates of association and dissociation of the lac re-pressor and its operator produce the disquieting conclusion that the rate constant for combination 7 x 10’ mol-I 1 s-’ is an order of magnitude faster than the calculated rates of diffusion of these polymers.303 After the repressors came the 0 fa~tor,~’~,~’~ followed quickly by p,306 these two being proteins which control the initiation and termination of mRNA synthesis.The enzyme under control RNA polymerase has the subunit com- position a,~~a which can be considered as the ‘core’ enzyme a,afi’-the minimal unit required for the synthesis of RNA-plus the factor. which greatly enhances the amount of RNA synthesis depending on the nature of the DNA template. An examination of the events following infection of E. coli by phage T4 shows that this 0 factor turns on RNA synthesis only from certain parts of the phage DNA. known as the pre-early genes whereas the core enzyme begins transcription 294 W. Bauer and J. Vinograd J. Mol. Biol. 1970 47 419. 295 B. M. J. Revet M. Schmir and J. Vinograd Nature New Biol. 1971 229 60. 296 M. Waring J. Mol. Biol. 1970 54 247. 297 M.Craig and I. Isenberg Biopolymers 1970 9 689. 298 V. M. Maher and W. C. Summers Nature 1970 225 68. 299 M. Ptashne Nature 1967 214 232. 300 W. Gilbert and B. Muller-Hill Proc. Nat. Acad. Sci. U.S.A. 1967 58 2415. 301 A. D. Riggs H. Suzuki and S. Bourgeois J. Mol. Biol. 1970 48 67. S.-Y.Lin and A. D. Riggs Nature 1970,228 1184. A. D. Riggs. S. Bourgeois and M. Cohn J. Mol. Biol. 1970,53 401. 3’4 R. R. Burgess A. A. Travers J. J. Dunn and E. K. F. Bautz Nature 1969 221 43. 3’5 A. A. Travers and R. R. Burgess Nature 1969 222 537. 306 J. W. Roberts Nature 1969 224 1168. G. M. Blackburn of the phage DNA indiscriminately and from both strand^.^^'*^^^ Once the pre- early genes of the phage have been transcribed they set about making their own phage-specific factor cT4which takes over the core enzyme from the bacterial c and initiates RNA synthesis from a second group of T genes the 'delayed-early' genes.309*310A second type of initiation factor I)~,has been discovered which stimulates the synthesis of ribosomal RNA.3 l1 While a definitive picture of how these factors work cannot yet be drawn it appears likely that c is involved in the pulling apart of the DNA strands to expose the bases for complementary base- pairing with the growing RNA.The termination factor p has not so easily yielded up the secrets of its action. Although it does control specific termination of RNA synthesis and ensures that the enzyme doesn't make RNA molecules of the wrong size it still appears that certain types of RNA termination can occur in the absence of p306 Lest this account appears to lay all control of nucleic acids only in the hands of proteins a final comment on cyclic AMP may provide a balance.In the fourteen years since its discovery the 3',5'-cyclic phosphate of adenosine has been recog- nised as a regulating factor par excellence.312 It has now emerged in the control system for transcription of the lac operon. Whereas the lac repressor provides negative control by turning off mRNA synthesis cyclic AMP activates a protein CAP which stimulates RNA polymerase to transcribe the functional genes of the lac ~ystem.~'~.~~~ It appears that the CT factor has the task of finding the right gene for transcription while the CAP-cyclic AMP complex restricts transcription to the correct strand.Cyclic AMP may not merely control our microbes but also constrain our mood-if the apparent correlation between mental state and the urinary level of cyclic AMP holds up to further in~estigation.~'~ Normal patients excrete between 1.4 and 3.2 pmol per day. Excretion above 3.4 pmol daily the result manic mood. Excretion less than 1.0pmol daily the result depression. And Micawber thought it was money ! 307 E. K. F. Bautz F. A. Bautz and J. J. Dunn Nature 1969 223 1023. 308 M. Sugiura T. Okamoto and M. Takanami Nature 1970 225 598. 309 A. A. Travers Nature 1970 225 1009. 310 D. A. Schmidt A. J. Mazaitis T. Kasai and E. K. Bautz Nature 1970 225 1012. 311 A. A. Travers R. I. Kamen and R. F. Schleif Nature 1970 228 748.312 I. Pastan and R. L. Perlman Nature New Biol. 1971 229 5. 313 G. Zubay D. Schwartz and J. Beckwith Proc. Nat. Acad. Sci. U.S.A. 1970 66 104. M. Emmer B. decrombrugghe I. Pastan and R. Perlman Proc. Nut. Acad. Sci. U.S.A. 1970 66 480. Y.H. Abdulla and K. Hamada Lancet 1970 i 378.

ISSN:0069-3030    

DOI:10.1039/OC9706700489

出版商:RSC    

年代:1970

数据来源: RSC

摘要:

16 Fatty Acids and Related Compounds By N. POLGAR The Dyson Perrins Laboratory Oxford 1 Reviews THE first volume' of 'Topics in Lipid Chemistry' published this year contains comprehensive reviews on cyclopropane and cyclopropene fatty acids,'" milk lipids,Ib structure determination of fatty esters by gas-liquid chromatography," hydrogenation with homogeneous and heterogeneous cata1ysts,Id optically active long-chain compounds and their absolute configurations," and mass spectro- metry of fatty acid derivatives.1s Topics reviewed elsewhere include the odd- numbered polyunsaturated fatty acids,2 the Cecropia juvenile hormones and their analog~es,~.~ and the my cob act in^.^ The occurrence structure and meta- bolism of the nonisoprenoid aliphatic hydrocarbons of bacteria have been re- viewed,6 with emphasis on recent work on the chemistry and biosynthesis of the hydrocarbons of Sarcina lutea.An issue' of Chern. and Phys. Lipids is devoted to the chemistry and metabolism of sphingolipids. 2 Isolation and Structure of Natural Acids Normal-chain natural products reported include 13~-hydroxy-cis-9,trans-1 1 -octadecadienoic acid* (the enantiomer of coreolic acid) and its lactone,' isolated from the seed oil of Monnina emarginata(Polygalaceae),a plant native to Uruguay ; this seed oil also contains small amounts of 13-0x0-trans-9-octadecenoic and 13-0x0-trans-9,trans-11-0ctadecadienoic acids.' A rich new source and useful material for the laboratory preparation of cis-15-tetracosenoic and cis-17-hexacosenoic acids is the fat of the commercially available Tropeolum speciosum seeds.'Topics in Lipid Chemistry,' ed. F. D. Gunstone Logos Press London vol. 1 1968; (a) W. W. Christie p. 1 ; (h) W. R. Morrison p. 51 ; (c) G. R. Jamieson p. 107; (d) E. N. Frankel and J. H. Dutton p. 161 ;(e)C. R. Smith jun. p. 277 v) J. A. McCloskey p. 369. H. Schlenk Progr. Chem. Fats and Lipids 1970 9 587. B. M. Trost Accounts Chem. Res. 1970 3 120. Yu. S. Tsizin and A. A. Drabkina Russ. Chem. Rev. 1970 39 498. G. A. Snow Bacreriol. Rev. 1970 34 99. ' P. W. Albro and J. C. Dittmer Lipids 1970 5 320. ' A collection of papers dedicated to H. E. Carter ed. C. C. Sweeley Chem. and Phys. Lipids 1970 5 (No. I) pp. 1-300. B. E. Phillips C.R. Smith jun. and L. W. Tjarks Biochim. Biophys. Acfa 1970 210 353. B. E. Phillips C. R. Smith jun. and L. W. Tjarks J. Urg. Chern. 1970,35 1916. lo C. Litchfield Lipids 1970 5 144. 524 N. Polgar There has been continued interest in various groups of branched-chain acids. From Mycobacterium phlei series of iso- anteiso- and (n-8)-methyl-substituted fatty acids," as well as monoenoic acids12 containing 20 to 27 carbon atoms including a series of 5-enoic acids have been isolated. A study on the structural relationship between the latter and the mycolic acids synthesised by the same organism led to the suggestion that the 5-enoic acids may serve as precursors for the mycolic acids." The mycolic acids from Corynebacterium hofmanii include a dienic C36 acid having the structure [l ; R' = Me.(CH,),CH:CH.(CH,),.; R2 = Me-(CH,),.CH :CH.(CH,),.] with ethylenic linkages in each alkyl chain. The lower my- colic acids (up to about C,,) previously thought to be characteristic of Cory- nebacteria have now been found also to occur as major components of the acylglucoses of Mycobacterium srnegmatis grown in the presence of gl~cose,'~ and also as dimycolate of trehalose ('cord factor') in Nocardia asteroides.' R .CH( OH)*CH R2C02 H (1) Other mycolic acids studied include those of Mycobacterium paratuberculosis.' Among the mycolic acids occurring in this organism are a series of dicarboxylic acids which are found to be present as esters derived from eicosan-2-01; such esters would represent according to a hypothetical biogenetic scheme presented earlier,' 'intermediates in the formation of dicarboxylic mycolic acids from higher ketomycolic acids.Comparative studies' of the molecular rotations shown by de- rivatives of various mycolic acids from Nocardia and Mycobacteria indicate that the previous assignment of 2R,3R configurations is valid for all the acids studied. 3 Synthesis Normal-chain Acids.-1 1 -Oxo[ 1,ll-' 4Cz]eicosanoic and 13-oxo[ 1,l 3-14C,]- docosanoic acids" have been synthesised by the acylation of cyclic enamines ; the 0x0-acids can be reduced to the corresponding saturated fatty acids. thus providing a method for the synthesis of long-chain fatty acids containing 14C in two positions. Methyl esters of polyunsaturated fatty acids labelled with tritium have been prepared by partial stereoselective reduction of the corresponding acetylenic esters with tritiated disiamylborane (bis-3-methyl-2-butylborane) followed by protonolysis with tritiated acetic acid.20 I.M. Campbell and J. Naworal J. Lipid Res. 1969 10 593. l2 C. P. Asselineau C. S. Lacave H. L. Montrozier and J.-C. Prome European J. Biorhem. 1970 14 406. I' M. Welby-Gieusse M. A. Laneelle and J. Asselineau European J. Biochem. 1970 13 164. 'P. J. Brennan D. P. Lehane and D. W. Thomas European J. Biochem. 1970,13 1 17. Is T. loneda E. Lederer and J. Rozanis Chem. and Phys. Lipids 1970 4 375. l6 M. A. Laneelle and G. Laneelle European J. Biochem. 1970 12,296. '' A. H. Etemadi and J. Gasche Bull. SOC.Chim. biol.1965 47,2095. C. Asselineau G. Tocanne and J.-F. Tocanne Bull. SOC.chim. France 1970 1455. l9 J. S. W. Hunter and R. J. Light Biochemistry 1970,9 4283. 2o D. S. Sgoutas H. Sanders and E. M. Yang J. Lipid Res. 1969,10,642. Fatty Acids and Related Compounds 525 Ten octadecadiynoic acids and the related cis,cis-and trans,trans-octadeca- dienoic acids,21 as well as some new C1 m-alicyclic and acyclic acids,22 including 9-pentadecenoic and 6,12-pentadecadienoic acids have been prepared. A synthesis of trans-3,cis-5-tetradecadienoic(megatomoic) acid the sex attractant of the black carpet beetle (Attagenus megatoma) starting from 1-decyne has been reported.23 The preparations and properties of conjugated oxo-octadecenoic24 and dioxo-octadecenoic acids' have been described.The 8- 9- and 10-pentadecynoic acids have been synthesised by refinements26 of the five-step Ahmad-Strong method. Racemic helenynolic acid (4) has been prepared2' from crepenynic acid (2) by epoxidation followed by base-catalysed rearrangement of the cis-epoxy-acid (3);the latter has been found to be present among the epoxy-acids of HeEichrysum bracteaturn seed oil and the synthesis described might represent the pathway by which helenynolic acid is produced by this seed oil from the crepenynic acid also present. Me.(CH,),C~CCH,.CHfCH.(CH,),CO,H (2) /*\ Me.(CH2)4CrCCH2CHC He( CH ,),-CO ,H Me.(C H J4-C fCCH f CH.CH(0H),(CH,),.CO H (4) Cycloalkane and Cycloalkene Acids-The first total syntheses of the prosta- glandins F2 (6 ; R = H) and E2 (7) as their naturally occurring optically active forms have been published;28 these syntheses represent an adaptation of the earlier described2' stereocontrolled syntheses of the racemic forms of these prostaglandins and involve resolution of the intermediate hydroxy-acid (5).The common intermediate the (+)-11,15-bistetrahydropyranyIether (6; R = tetrahydropyranyl) of prostaglandin F2, has now also been employed3' for total syntheses of the natural forms of the prostaglandins F, (8) and El (9) (the first total synthesis of the latter had been published in 19693'). 21 F. D. Gunstone and M. Lie Ken Jie Chem. and Phys. Lipids 1970,4 1. 22 A. K. Sen Gupta and H. Peters Chem. and Phys. Lipids 1969,3 371. 23 J. 0.Rodin M.A. Leaffer and R. M. Silverstein J. Org. Chem. 1970 35 3152. 24 A. Tubul J. Arnoux E. Ucciani and M. Naudet Chem. and Phys. Lipids 1970,4,208. 25 M. Naudet J. Arnoux and A. Tubul Chem. and Phys. Lipids 1970,4 217. 26 D. R. Howton and R. A. Stein J. Lipid Res. 1969 10 631. 27 H. B. S. Conacher and F. D. Gunstone Lipids 1970,5 137. 28 E. J. Corey T. K. Schaaf W. Huber U. Koelliker and N. M. Weinshenker J. Amer. Chem. Soc. 1970,92 397. 29 E. J. Corey N. M. Weinshenker T. K. Schaaf and W. Huber J. Amer. Chem. SOC. 1969,91 5675. 30 E. J. Corey R. Noyori and T. K. Schaaf J. Amer. Chem. SOC.,1970,92,2586. 31 E. J. Corey I. Vlatias and K. Harding J. Amer. Chem. Soc. 1969 91 535. 526 N. Polgar HC Other syntheses published in this field include total syntheses of the (-t)-prostaglandins E2 and F2=via tricarbocyclic intermediate^,,^ and of the methyl ester of (*)-prostaglandin E (distinguished from prostaglandin E2 by an addi- tional cis-double bond between C-17 and C- 18) through endo-bicyclohexane intermediate^.^^ A total synthesis34 of prostaglandin El incorporating stereo- chemical control at the nuclear chiral centres involves construction of a cis-hydrindanone system in which a thermodynamically predominant exo-side- chain orientation prevails.Details are available35 of the synthesis36 of methyl sterculate (10; n = 7) from methyl stearolate and diazoacetic ester. Another synthesis37 involves photolysis of diazomethane in the presence of methyl stearolate. Its lower homologue methyl malvalate (10; n = 6) has been synthesised by several procedures3* including a route via the intermediate (1 1); the latter was obtained by reaction of 1-chlorohexadec-7-yne with ethyl diazoacetate.Syntheses adaptable for 32 E. J. Corey 2.Arnold and J. Hutton Tetrahedron Letters 1970 307. 33 U. Axen J. L. Thompson and J. E. Pike Chem. Comm. 1970,602. 34 D. Taub R. D. Hoffsommer C. H. Kuo H. L. Slates Z. S. Zelawski and N. L. Wendler Chem. Comm. 1970 1258. 35 W. J. Gensler M. B. Floyd R. Yanase and K. M. Pober J. Amer. Chem. SOC.,1970 92 2472. 36 Cf. Ann. Reports (B) 1969 66 546. 37 E. R. Altenburger J. W. Berry and A. J. Deutschman J. Amer. Oil.Chemists' SOC. 1970 47 77. 38 W. J. Gensler K. W. Pober D. M. Solomon and M. B. Floyd J. Org. Chem.1970,35 2301. Fatty Acids and Related Compounds 527 preparing methyl malvalate labelled with 14C in various positions including the cyclopropene methylene group are also described.39 FFt2 Me-(CH,),-C=C.(CH,),.CO,Me (10) CH.CO2 H /\ Me.(CH,),.C=C.(CH,),Cl (1 1) Branched-chain Acids.-~~,4~,6~,8~-Tetramethyloctacosanoic acid (13) a major component of the branched-chain acids of tubercle bacilli has been synthesised4' via methyl 2~,4~,6~-trimethyldodec-ll-enoate (12; n = 2)41 and 2~,4~,6D,8~- tetramethyltetradec-13-enoate(12 ;n = 3) followed by chain-lengthening of the latter. D CH :CH-(CH,),.(CHMeCH,),,CHMe.CO,Me-CO,Me (12) D D Me.(CHz),,-(CHMeCH,)3CHMe.C0,H (13) A stereochemically controlled synthesis42 of methyl natural bixin (15) involves 5-methoxycarbonyl-3-methylpenta-cis-(Z)-2-~runs~~)~-dien-l -a1 (14) as the key intermediate.This synthesis confirms the cis-(Z)-4-structure previously assigned on the basis of n.m.r. studies ;it also represents the first stereochemically controlled direct total synthesis of a carotenoid containing a methylated cis-double bond. MeOZC MeOzC (15) A new stereospecific route43 to the Cecropia juvenile hormones (16) and (17) utilises a single intermediate for both compounds. Other recent syntheses include 39 W. J. Gender K. W. Pober D. W. Solomon R. Yanase. and M. B. Floyd Chem. Comm. 1970,287. 40 G. Odham E. Stenhagen and K. Waern Arkiv Kemi 1970,31 533. 41 Cf. Ann. Reports (B) 1969,66 547. 4z G. Pattenden J.E. Way and B. C. L. Weedon J. Chem. SOC.(0,1970,235. 43 E. J. Corey and H. Yamamoto J. Amer. Chem. SOC., 1970,92,6636. 528 N. Polgar some highly stereoselective to the hormone (16) and a stereospecific route47 to a biologically active isomer of the C17 hormone (17). A short non- stereospecific synthesis recently reported48 provides a synthetic approach to the pure hormones as well as their stereoisomers. C r r Et.CMeCH.(CH,),CR :CH+(CH,),CMe:CHC0,Me \/ 0 (16) R = Et (17) R = Me The preparation of a series of tritium-labelled long-chain iso-acids by anodic syntheses has also been described.49 4 Reactions A soluble enzyme preparation from a pseudomonad has been shown to catalyse the stereospecific hydration of cis-double bonds between C-9 and C-10 in oleic5' as well as in linoleic acid5' to yield the corresponding 10D-hydroxy-acids.The same enzyme system has also been found5' to catalyse the stereospecific con- version of cis- and trans-9,lO-epoxystearic acids to threo-and erythro-9,lO- dihydroxystearic acids respectively. The Diels-Alder addition products of ethylene and trans,trans-9,11 -octa- decadienoic acid have been subjected to oxidation with per acid^^^ and ozone,54 and the resulting products investigated. The effect of solvents upon the cyclisa- tion of methyl ricinelaidate by solvolysis of its tosylate has been studied and the mechanism disc~ssed.~ The formation of 1,4-epoxides from methyl linoleate and related esters by reaction with toluene-p-sulphonic acid and an appropriate solvent has been de~cribed.~~ The oxymercuration4emercuration of long-chain unsaturated esters has been utilised for preparative procedures ;57 the presence of a substituent (OH OMe OAc) has been found to affect the proportion of the resulting isomeric products and in some cases give rise to novel products.44 R. J. Anderson C. A. Henrick and J. B. Siddall J. Amer. Chem. SOC.,1970,92 735. 45 E. E. van Tamelen and J. P. McCormick J. Amer. Chem. Soc. 1970,92,737. 46 W. S. Johnson T. J. Brocksom P. Loew D. H. Rich L. Werthemann R. A. Arnold Tsung-tee Li and D. J. Faulkner J. Amer. Chem. SOC.,1970,92 4463. 47 E. J. Corey and H. Yamamoto J. Amer. Chem. SOC.,1970,92,6637. 48 J. A. Findlay W. D. MacKay and W. S.Bowers J. Chem. SOC.(C),1970 2631. 49 I. Bjorkhem and H. Danielsson European J. Biochem. 1970 14,473. W. G. Niehaus jun. A. Kisic D. J. Bednarczyk and G. J. Schroepfer jun. J. Biol. Chem. 1970,245 3790. '' G. J. Schroepfer jun. and W. G. Niehaus jun. J. Biol. Chem. 1970,245 3798. 52 W. G. Niehaus jun. A. Kisic A. Torkelson D. J. Bednarczyk and G. Schroepfer jun. J. Biol. Chem. 1970 245 3802. 53 E. J. Dufek L. E. Gast and J. P. Friedrich J.Amer. Oil Chemists' Soc. 1970,47 47. 54 E. J. Dufek J. C. Cowan and J. P. Friedrich J. Amer. Oil Chemists' SOC.,1970,47 51. 55 E. Ucciani A. Vantillard and M. Naudet Chem. and Phys. Lipids 1970 4 225. 56 G. G. Abbot F. D. Gunstone and (in part) S. D. Hoyes Chem. and Phys. Lipids 1970 4 351. 57 F. D. Gunstone and R.P. Inglis Chem. Comm. 1970 877. Fatty Acids and Related Compounds 529 Methods used for the preparation of epiminostearates have been compared ;5 it is found that the addition of NN-dichlorourethane to olefins results in mixtures of cis- and trans-aziridines whereas the iodine isocyanate method is stereo- specific cis-olefins giving rise to cis- and trans-olefins forming trans-aziridines. Reaction of thallium(II1) acetate with an excess of aliphatic carboxylic acids results in the formation of the corresponding a-acyloxy-acids.5 Undec-lO-enoic acid in the presence of polyphosphoric acid has been shown6' to yield a mixture of 2-n-hexylcyclopent-2-enone and 2-n-pentylcyclohex-2-enone. 5 Glycerol and Diol Lipids The structures (18; X = Me R = 11,12-methyleneoctadecanoyl)and (18; X = H R = 10-methyloctadecanoyl) derived from diol esters of ornithine have been proposed61 for lipids isolated from BruceIla melitensis and Mycobac-terium bouis respectively.Me.(CH2)1,-CH(OH).CH,CONHCHCO,CHX.CH,OR I (CH213NH2 (18) Stereospecific syntheses of optically active unsaturated 1,2-diglycerides ilia 1,2-isopropylidene-sn-glycero1-3-~~~-trichloroethylcarbonate have been repor- ted.62 Dihydroxyacetone has been to be a convenient starting material for the synthesis of 1,3-diglycerides since it is readily acylated with fatty acyl chlorides and the central keto-group is rapidly reduced by borohydride in tetrahydrofuran solution. The mass spectra of deuteriated glycerol 1,3-distearates have been The diesters of 2,3-dihydroxy-octadecane,isolated from the preen gland of the green pheasant have been Neutral diol plasmalogens have been synthesised.66 The positional distribution of fatty acids in the phospholipids and triglycerides of M.smegmatis and M. bo~is,~' as well as the structure of the phospholipids of Arthrobacter simplex68 containing 2-hydroxy-acids have been investigated. A procedure has been described for the separation of phosphatidylcholines (lecithins) according to the number of ethylenic bonds in their fatty acid residues;69 the 58 T. A. Foglia G. Maerker and G. R. Smith J. Amer. Oil Chemists' Soc. 1970,47 384. E. C. Taylor H. W. Altland and G. McGillivray Tetrahedron Letters 1970 5285. 6o M. F. Ansell and T. M. Kafka Tetrahedron 1969 25 6025." J.-C. Prome C. Lacave and M. A. Laneelle Compt. rend. 1969 269C. 1664. 62 F. R. Pfeiffer C. K. Miao and J. A. Weisbach J. Org. Chem. 1970,35,221. 63 P. H. Bentley and W. McCrae J. Org. Chem. 1970 35 2082. " A. Morrison M. D. Barratt and R. Aneja Chem. and Phys. Lipids 1970 4 47. h5 K. Saito and M. Gamo J. Biochem. (Tokyo) 1970,67,841. " J. G. Kramer and H. K. Mangold Chem. and Phys. Lipids 1970 4 332. " R. W. Walker H. Barakat and J. G. C. Hung Lipids 1970,5 684. 68 I. Yano Y.Furukawa and M. Kusunose Biochim. Biophys. Acta 1970,210 105. 69 R. J. King and J. A. Clements J. Lipid Res. 1970 11 381. 530 N. Polgar procedure involves chromatography ofthe mercuric acetate adducts on a column of partially methylated dextran (Sephadex LH-20).A general synthesis7'v7 of glycerophospholipids involves the direct phosphory- lation of the appropriate alcohols with phosphatidic acids using tri-isopropyl- benzenesulphonyl chloride as a condensing agent. 2-Acylphosphoglycerides have been prepared7 by a procedure involving phosphorylation of 1-alkenyl-2-acylglycerols.Syntheses of 2-monoacylphos-phoglycerides with a 14C-labelled unsaturated acyl group from their 1,2-diacyl- derivatives by hydrolysis of the 1-acyl group with purified lipase preparations are also described. A 3-acyl-sn-glycero-l-phosphorylcholine, representing an antipode of the naturally occurring lysophosphatidylcholines has been s~nthesised~~ from 3,4-isopropylidene-~-mannitol. Other syntheses of model compounds include those of various analogues of deoxylysophosphatidyIcholines,75phosphogly-cerides derived from acetylenic and cyclopropane fatty and a synthesis of threonine phosph~glycerides.~ A procedure78 for the preparation of 1-alkyl-2-acylphosphoglycerides labelled with [l-14C]oleic acid is based upon the acyla- tion of the cadmium chloride complex of 1-alkylglycero-3-phosphorylcholine.In the course of studies of the phosphonolipids a procedure for the synthesis of phosphonic acid analogues of the racemic as well as both enantiomeric forms of phosphatidyl(N-methy1)ethanolamineshas been developed ;79 phosphonic acid analogues with a P-C bond of phosphatidic acids have also been synthesised.80 6 Sphingolipids A stereospecific synthesis of sphinganine (19)(previously named dihydrosphingo- sine) from the readily available 3-amino-3-deoxy-l,2 :5,6-di-O-isopropylidene-a-D-allofuranose has been described,8 and the occurrence of sphinga-4,8-dienine in oyster sphingoglycolipid reported.82 D D Me.(CH,) ,.CH(OH).CH(N H,).CH ,OH (19) 'O R.Aneja J. S. Chadha and A. P. Davies Biochim. Biophys. Acta 1970,218 102. 71 R. Aneja and A. P. Davies Chem. and Phys. Lipids 1970 4 60. 72 H. Eibl and W. E. M. Lands Biochemistry 1970,9 423. 73 A. J. Slotboom G. H. de Haas G. J. Burbach-Westerhuis and L. L. M. van Deenen Chem. and Phys. Lipids 1970,4 30. 74 H. Eibl and 0. Westphal Annalen 1970 738 161. '' H. Eibl and 0. Westphal Annalen 1970 738 170. 76 D. L. Turner M. J. Silver E. Baczynski R. R. Holburn S.F. Herb and F. E. Luddy Lipids 1970 5 650. 77 J. W. Moore and M. Szelke Tetrahedron Letters 1970 4423. 78 A. Poulos J. Lipid Res. 1970 11,496. '' E. Baer and S. K. Pavanaram Canad. J. Biochem. 1970,48,979. *O E. Baer and H. Basu Canad. J. Biochem. 1970,48 1010. " E. J. Reist and P. H. Christie J. Org. Chem. 1970 35 3521. 82 A. Hayashi and T. Matsubara Biochim. Biophys. Acta 1970 202 228. Fatty Acids and Related Compounds 531 A sphingolipid of the anaerobic bacterium Bacteroides mefaninogenicus has been foundB3 to be a ceramide phosphorylglycerol phosphate. Studies of various synthetic ceramides by g1.c.-mass spectrometry of their trimethylsilyl ether derivatives have been de~cribed.~~’~ A sensitive estimations6 of sphing-4-enine (previously named sphingosine) involves fluorescence measure- ments of a complex formed with 1-naphthylamino-4-sulphonicacid.7 Glycolipids The structures of acylglucoses isolated from Corynebacteria and M ycobacteria grown in the presence of glu~ose,’~ as well as those of the diesters of trehalose (‘cord factors’) produced by Nocardia asteroides and N. rhodochrous’ have been investigated and further studies reported on the complex glycolipids from Myco bacteria8 7-’ and N ~cardia.~~.~ A synthesis of phosphatidylcholine analogues derived from sugar alcohols has been de~cribed.’~ 8 Other Natural Compounds Related to Fatty Acids Further studies of the methyl-branched hydrocarbons occurring in blue-green algae have been reported.”-’ The presence of homologous series of mono- di- and trimethyl-substituted hydrocarbons in the egg of the tobacco hornworm Manduca sexta has been demonstrated,’* the branching points of the di- and tri-methylalkanes are near the centre of the alkyl chain and separated by three carbon atoms.Homologous series of long-chain 3,7,11-and 4,8,12-trimethyl- alkanes are the major constituents of the cuticular alkanes of the ant Attu colombicu.” In studies of the stereochemistry of the homologous phthiocerols A (20; n = 20 and 22 X = OH Y = OMe R = Et) and B (20;n = 20 and 22 X = OH Y = OMe R = Me) constituents of tubercle bacilli conversion of the phthiocerols A into the optically active hydrocarbons (20; n = 20 and 22 X = H Y = H R = Et) resulted in the assignment”’ of S-configuration to the asymmetric ” D.C. White and A. N. Tucker Lipids 1970,5 56. 84 S. Hammarstrom B. Samuelsson and K. Samuelsson J. Lipid Res. 1970 11 150. a5 S. Hammarstrom J. Lipid Res. 1970 11 175. a6 L. Coles and G. M.Gray J. Lipid Res. 1970 11 164. ” J. Markovits and E. Vilkas Biochim. Biophys. Acta 1969 192,49. I. Azuma Y. Yamamura and A. Misaki J. Bacteriol. 1969 98 331. 89 C1. Amar-Nacash and E. Vilkas Bull. SOC.Chim. biol. 1970,52 145. 90 F. Kanetsuma and G. S. Blas Biochim. Biophys. Acta 1970 208 434. 91 P. V. Narasimh Acharya and D. S. Goldman J. Bacteriol. 1970 102 733. q2 M. Guinand M. J. Vacheron and G. Michel F.E.B.S. Letters 1970 6 37. 93 M. A. Laneelle and J. Asselineau F.E.B.S. Letters 1970 7 64. y4 H. Eibl and 0.Westphal Annafen 1970 738 174. 95 J. Han and M. Calvin Chem. Comm. 1970 1490. 96 E. Gelpi H. Schneider J. Mann and J. Oro Phytochemistry 1970 9,603. 97 S. W. G. Fehler and R. J. Light Biochemistry 1970,9,418. ” D. R.Nelson and D. R. Sukkestad Biochemistry 1970,9,4601. ” M. M. Martin and J. G. MacConnell Tetrahedron 1970 26 307. loo K. Maskens and N. Polgar Chem. Comm. 1970 340. 532 N. Polgar centre bearing the methyl branch (C-4of the phthiocerols A). Moreover conver- sion of the phthiocerols A and B into the methoxyphthiocerans (20; n = 20and 22 X = H Y = OMe R = Et) and (20;n = 20 and 22 X = H,Y = OMe R = Me) respectively and comparison of these methoxy-derivatives with synthetic compounds showed that the centres bearing the methoxy-group have R-configuration.' The opposite configurations have been deduced' O2 by the method of molecular-rotation differences with calculations of rotatory powers based upon Brewster's rules; the asymmetric centres of the P-diol group (C-9 and C-11 ofthe phthiocerols A) were assigned R,R-configurati~ns.'~~ Me.(CH,);CHCH,CH.(CH,),.CHCHR 'x It I X Me Y Terrestrol (3,7,1l-trimethyldodeca-6,lO-dienol),isolated from male bumble- bees has been shown to have L-configuration'04 by a study of the cyclic acetals prepared from the corresponding aldehyde and D-( -)-propane- 1,2-diol.In studies of the chlorosulpholipids a novel class of lipids discovered in Ochromonas danica the most abundant sulpholipid of this organism has been shown to be a disulphate of 2,2,11,13,15,16-hexachloro-n-docosane-1,14-dio1.105 Cyanolipids consisting of long-chain fatty acids esterified with an unsaturated isoprenoid hydroxy- or dihydroxy-nitrile have been isolated from the seed oils of various plants.'06,107 9 Miscellaneous A methodlo8for establishing the position of double bonds in mono- and poly- enoic long-chain esters involves reduction of their methoxymercuration products with sodium borohydride followed by combined g.1.c.-mass spectrometry of the resulting methoxylated esters.The mercuric acetate adducts of unsaturated fatty acids have been shown'0g to be suitable for determination of the cis:trans ratio by n.m.r. spectroscopy. A mass spectrometric method" for discriminating between methyl esters of isomeric monoenoic and cyclopropanoid fatty acids as well as between those derived from normal iso- and anteiso-acids involves measurements of the ratio of the intensity of the parent molecular ion P to that of the P-32 ion.lo' K. Maskens and N. Polgar Chem. Comm. 1970 673. lo' M. Welby-Gieusse and J. F. Tocanne Tetrahedron 1970 26,2875. *03 J. F. Tocanne Bull. SOC.chim. France 1970 750. Io4 S. Stallberg-Stenhagen Acta Chem. Scand. 1970,24 358. Io5 J. Elovson and P. R. Vagelos Biochemistry 1970 9 31 10. lo6 K. L. Mikolajczak C. R. Smith jun. and L. W. Tjarks Lipids 1970 5,672. lo' K. L. Mikolajczak C. R. Smith jun. and L. W. Tjarks Lipids 1970,5 812. lo* P. Abley F. J. McQuillin D. E. Minnikin K. Kusamran K. Maskens and N. Polgar Chem. Comm. 1970 348. lo' K.Schaumburg Lipids 1970 5 505. I. M. Campbell and J. Naworal J. Lipid Res. 1969 10 589. Fatty Acids and Related Compounds The g.1.c. and mass spectral properties of perdeuteriated fatty-acid methyl esters (including esters of various methyl-branched and unsaturated long-chain acids) from Scenedesrnus obliquus which had been grown in D,O have been stu- died."' The g.1.c. equivalent chain lengths have been deterrnined'l2 for a number of isomeric methyl octadecenoates and octadecynoates. The t.1.c. and g.1.c. properties of some di-unsaturated C esters,' l3 as well as of the octadecenyl compounds' ' (alcohols acetates trifluoroacetates aldehydes and hydrocarbons) derived from the methyl cis-octadec-2- to -17-enoates have been investigated.The n.m.r. spectra of a number of octadecadiynoic acids and of the derived methyl cis,cis-and trans,trans-octadecadienoates,' ' as well as of some conjugated fatty-acid methyl esters' have been studied. Gel permeation chromatography on Sephadex LH-20 has been shown"' to be useful for the separation of various hydroxy-lipids e.g. 1,2- and 1,3-diglycerides from long-chain alcohols or alkyl ethanediol mono-ethers from cholesterol. 'I1 G. Wendt and J. A. McCloskey Biochemistry 1970,9,4854. l2 C. R. Scholfield and H. J. Dutton J. Amer. Oil Chemists' SOC. 1970,47 1. F. D. Gunstone and M. Lie Ken Jie Chem. and Phys. Lipids 1970,4 131. I l4 F. D. Gunstone and M. Lie Ken Jie Chem. and Phys. Lipids 1970,4 139. F. D. Gunstone M. Lie Ken Jie and R. T. Wall Chem.and Phys. Lipids 1969,3,297. 0.Suzuki T. Hashirnoto K. Hayarnizu and 0.Yamamoto Lipids 1970,5 457. 'I7 M. Calderon and W. J. Baumann J. Lipid Res. 1970 11 167.

ISSN:0069-3030    

DOI:10.1039/OC9706700523

出版商:RSC    

年代:1970

数据来源: RSC

摘要:

17 Biosynthesis By J. STAUNTON University Chemical Laboratory Lensfield Road Cambridge CB2 IE W RELATIVELY few new biosynthetic reactions have been discovered this year and most of the published work has deaIt with the stereochemistry and mechanism of known biosynthetic reactions. Mevalonic Acid.-The biosynthesis of mevalonic acid (3) is known to involve reduction of the coenzyme-A ester of hydroxymethylglutaric acid (1)by two moles of NADPH. The corresponding aldehyde might be expected to be an inter- mediate in this process but in earlier experimental tests this compound did not fit the criteria for a true intermediate. It has now been shown' that the corre- sponding thiohemiacetal (2) is rapidly reduced by the enzyme and is therefore a probable intermediate at the aldehyde level of oxidation.HO HO (1) (2) (3) This separation of the two reduction steps was then exploited' for the prepara- tion of mevalonic acid stereospecifically labelled with tritium at C-5,by reducing the thiohemiacetal with tritiated NADPH. The configuration at C-5 was deter- mined by administering a mixture of the tritiated compound with [2-14C]-mevalonate to a Claviceps culture. The resultant agroclavine (4 R = Me) and elymoclavine (4:R = CH'OH) each incorporated activity to show an isotopic (4) ' J. Retey E. von Stetten U. Coy and F. Lynen European J. Biochem. 1970 15 72. P. Blattmann and J. Retey Chem. Comm. 1970 1394. 536 J. Staunton ratio corresponding to complete retention of the tritium. The tritium activity was proved by degradation to reside as expected on C-10.In a parallel feeding of the previously prepared [(5S),5-3HJmevalonic acid the opposite result was obtained and all the tritium activity was lost in the biosynthesis of the two alkaloid^.^ Therefore in the reduction of the thiohemiacetal the incoming tritium must take up the 5pro-R configuration to yield the hitherto unknown [(5R),5-3H,]mevalonic acid. Two independent syntheses4,’ of this compound were published simultaneously and the preparation of this isomer means that there is now available for use in biosynthetic studies the complete series of six possible mevalonic acids stereospecifically labelled with tritium at C-2 C-4 and C-5 respectively. Monoterpenes.-The most important advances in this area continue to be made in the study of the biosynthesis of loganin (6) and related terpenes largely as a by-product of the work on indole alkaloid biosynthesis.Both nerol (5) and geraniol the 2,3-trans isomer are known to serve as precursors of loganin. It has now been shown by both carbon-6 and tritium-labelling’ studies that the corresponding 10-hydroxy derivatives also serve as precursors and the efficiency in each case is comparable to that of the parent compound. The 14C study was particularly informative in that the two hydroxy-compounds were fed separately and both were found to be incorporated. This shows that the isomerisation of the 2,3-double bond can occur after hydroxylation at C-10. Another important result to emerge from the I4C study was the demonstration that the label from C-9 of the hydroxy-compounds was equally distributed between C-3 and C-8 of loganin.The mechanism of the equilibration is of much interest. Clearly this reaction can occur after C-10 of geraniol has undergone oxidation and it is suggested that it may take place cia enolisation of a dialdehyde intermediate. Little progress has been made on the biosynthesis of other cyclic monoterpenes and the factor which continues to hold up progress is the low incorporation ob- served for the usual terpene precursors in most monoterpene producing plants. The difficulty can be illustrated by reference to recent work on the biosynthesis of M. Seiler W. Acklin and D. Arigoni Chem. Comm. 1970 1394. J. W. Cornforth and F.P. Ross Chem. Comm. 1970 1395. A. I. Scott G. T. Phillips P. B. Reichardt and J. G. Sweeny Chem. Comm. 1970 1396. S. Escher P. Loew and D. Arigoni Chem. Comm. 1970,823. A. R. Battersby S. H. Brown andT. G. Payne Chem. Comm. 1970 827. Biosynthesis 537 a range of cyclic monoterpenes including thujone (7)8 and camphor (Q9 The incorporation levels of [2-'4C]mevalonic acid were generally exceptionally low A (7) (0.001-0.2%). The labelling pattern of both thujone and camphor was deter- mined by degradation and it was shown that for each compound most of the activity was located in the starred position. This carbon would be expected in each case to be derived from the methylene group of isopentenyl pyrophosphate and on this basis it would appear that the mevalonic acid is converted to this intermediate but not to dimethylallyl pyrophosphate in the plants used in this investigation.This pattern of incorporation into only one of the two C,-units is in contrast to that observed in the cyclopentane monoterpenes. However the differential incorporation is probably not of fundamental significance but may only be a further reflection of the low efficiency with which mevalonic acid reaches the active sites of terpene synthesis. The first group to discover a solution to this incorporation problem should have a rewarding time in the study of this very interesting area of biosynthesis. The break-through may come from the development of a potent cell-free system or possibly from the discovery of a more co-operative plant.In this respect it is encouraging to note that the petals of the hybrid rose Lady Seaton gave a good incorporation of mevalonic acid and this fact has been exploited in a study of geraniol and nerol (5) biosynthesis." For both compounds the activity from [2-'4C]mevalonic acid was incorporated to produce equal labelling of the two isoprene units. In feeding experiments with the appropriate tritiated mevalonic acids it was found that for nerol as well as geraniol the 4pro-R hydrogen was retained in both units whereas the 4pro-S hydrogen was lost. The retection of the 4pro-R hydrogen at C-2 of nerol suggests that the cis-2,3-double bond was originally generated in the trans configuration and therefore that nerol is derived via geraniol.This isomerisation has been inferred from earlier work on indole alkaloid biosynthesis but this investigation provides the first direct proof of this interesting point. Sesquiterpenes-In earlier work on the biosynthesis of the tricothecane anti- biotics represented here by tricodermol (lo) it was shown that farnesyl pyro- phosphate was incorporated and the evidence suggested that a 6,7-cis isomer was D. V. Banthorpe J. Mann and K. W. Turnbull J. Chem. SOC.(0,1970,2689. ' D. V. Banthorpe and D. Baxendale J. Chem. SOC.(C) 1970,2694. lo M. J. 0.Francis D. V. Banthorpe and G. N. J. Le Patourel Nature 1970,228 1005. 538 J. Staunton involved. However present work' '*12 on the pattern of incorporation of activity from mevalonic acid labelled at various positions with carbon and tritium supports a biosynthesis via a 6,7-trans precursor.I (9) The distinction can be made on the basis of the labelling pattern in ring A. The I4C-labelling pattern would provide the more reliable evidence but in the preliminary studies reported so far only the tritium pattern has been investigated. The most direct piece of evidence came from the tricodermol derived from [(4R),4-3H,]mevalonic acid. The isotopic ratio corresponded to the retention of two tritium atoms and it was shown directly by degradation that one of these tritium atoms resides at C-10 in agreement with a 6,7-trans precursor folded as in (9). It can be speculated that gossypol(l2) is biosynthesised by the linking of two separately formed sesquiterpene units.Each of these units might be expected to derive from a farnesol derivative which in principle could be folded in one of several ways to generate the required carbon skeleton. The folding pattern (11) has received support from administration of [2-14C]farnesyl pyrophosphate to a cotton plant h~mogenate.'~ It was found by degradation that all the activity of the isolated gossypol was located in the two residues corresponding to C-2 with C-3 and C-1 1. Further evidence for the all-cis precursor came from feeding the four possible double-bond isomers of farnesyl pyrophosphate. Only the two isomers having a cis-double bond at C-6 were incorporated and of these the cis,cis isomer was the more efficient precursor. Preliminary results on the pattern of incorporation of activity from [1-'4C]- acetate and [2-'4C]me~alonate into the fungal metabolite helicobasidin (13) suggest that three units of mevalonic acid are incorporated and therefore that I' B.Achilladelis P. M. Adams and J. R. Hanson Chem. Comm. 1970 51 I. P. M. Adams and J. R. Hanson Chem. Comm. 1970 1569. l3 P. F. Heinstein D. L. Herman S. B. Tove and F. H. Smith J. Biof. Chem. 1970 245,4658. Biosynthesis 539 farnesyl pyrophosphate may be a prec~rsor.'~ As would be expected on this basis the cyclopentane ring contained two thirds of the activity from mevalonic acid and the benzoid ring one third. Diterpenes.-In the biosynthesis of the gibberellins the main interest of current work is centred on the sequence of steps by which ring B of the kaurene skeleton represented here by a possible intermediate 7P-hydroxykaurenoic acid (14 ; X = H) undergoes contraction to form the five-membered ring B of the gibberel- lins represented by gibberellic acid (15).There is evidence that the process involves the migration indicated in the diagram and it would be argued on stereoelectronic grounds that for a concerted reaction the leaving group X at C-6 would be in the p-orientation (equatorial) as indicated. (14) (15) The stereochemistry of the reaction at C-6 has been probed by feeding mevalonic acid and geraniol labelled in each case on the carbon which generates C-6 of the kaurene skeleton." Thus when [2-'4C,2-3H,]geraniol was fed it was expected to label the two hydrogen atoms of the C-6 methylene of early kaurene intermediates such as (14; X = H) and ultimately the hydrogen at C-10 of gibberellic acid.In fact the gibberellic acid was found to have an isotopic ratio corresponding to the retention of one of the two hydrogens on C-2 of geraniol and it was shown by degradation that the tritium resided at the expected position. This result proves indirectly that one of the two hydrogens at C-6 of the kaurene skeleton survives the rearrangement step to be retained at C-10 of gibberellic acid. This experiment was then followed by a feeding of [(5R),5-3H,]mevalonic acid which would be expected to label only the P-hydrogen of the C-6 methylene in the kaurene intermediates. It was found that this time the C-10 position of gibberellic acid was devoid of tritium.These results interlock to suggest that it is the 6a-hydrogen which is retained through the sequence of reactions leading from (14; X = H) to (15) and that the 6P-hydrogen is lost. In principle this reaction could involve a direct oxidative removal of the p-hydrogen from C-6 in the ring-contraction step. A more attractive reaction sequence would involve a preliminary hydroxylation at C-6 (with the normal retention of configuration) to give the 6P-hydroxy derivative (14; X = OH). The hydroxy-group or a suitable derivative would then serve as a good leaving group for the ring-contraction step. Unfortunately this dihydroxy-acid failed l4 R. Bentley and D. Chen Phytochernistry 1969,8,2171. l5 R. Evans J.R. Hanson and A. F. White J. Chern. SOC.(0,1970,2601. 540 J. Staunton to incorporate into gibberellic acid when tested as a precursor although it was found to serve as a very efficient precursor of fujenal (16).16 A negative result was also observed” for the incorporation of the trio1 corresponding to (14; (16) X = OH) in which the carboxy-group is replaced by a CH20H group so that further work will be required to discover the detailed reaction scheme involved in the ring contraction. Steroids.-This is probably the most active area of biosynthetic study at present. However a comprehensive account of recent trends in the work on steroid biosynthesis was given in last year’s report’* and it will be reasonable this year to concentrate on cholesterol biosynthesis.Much of the work on other steroids follows very closely the pattern already established in the study of cholesterol. Further information has been obtained on the sequence of steps leading from squalene to lanosterol. There is much evidence from past incorporation studies in cell-free systems to show that squalene is converted to the 2,3-oxide (17; 24 B. E. Cross J. C. Stewart and J. L. Stoddart Phytochernistry 1970 9 1065. ” P. R. Jefferies J. R. Knox,and T. Ratajczak Tetrahedron Letters 1970 3229. J. Staunton Ann. Reports (B) 1969 66 555. Biosynthesis 541 R = Me) which then undergoes enzyme mediated cyclisation. On mechanistic grounds it was argued that the initial cyclisation product could be the carbonium ion (18;R = Me) which can then lead to lanosterol (19 ;R = Me) by the series of hydride shifts and methyl migrations as indicated.Direct evidence to show that the oxide is a true intermediate in this process has now come from experiments with heat-treated microsomes.'9 The cyclase activity is selectively destroyed by heat and now on incubation with squalene the oxide accumulates instead of lanosterol. There has been much interest in the influence of structure on reactivity in the cyclisation and rearrangement steps respectively and in a continuation of this line of investigation the oxide (17; R = H) which lacks the methyl group at C-10 has been incubated with the enzyme.20 It was found to be converted efficiently to the corresponding lanosterol derivative (19; R = H).Therefore the steric interactions of this methyl with the rest of the molecule do not provide a crucial driving force for either the cyclisation or the rearrangement step. It is interesting to note that while the cyclase is very sensitive to alteration of the pattern of substitution on the epoxide ring of (17) major modification can be carried out at various sites in the rest of the molecule without causing a serious loss of efficiency in the cyclisation step. The subsequent conversion of lanosterol to cholesterol (20) requires the saturation of the side-chain double bond and a challenging problem is posed 24 by the stereochemistry of addition of hydrogen to C-25 in this process. A method of selectively attacking one of the two enantiotopic methyl groups attached to C-25 in cholesterol is required and a neat solution has been achieved by subject- ing cholesterol to a microbiological reaction in which the 25pro-S methyl was specifically hydroxylated to form a primary alcohol.21 The cholesterol derived from [2-'4C]mevalonate was now converted to the hydroxy derivative and it could then be established by further chemical degradation that the CH,OH group carried 17% of the total activity.This proves that the 25pro-S methyl carries one of the five carbon labels in cholesterol derived from [2-'4C]mevalonic acid and it is inferred that the 25pro-R methyl group is derived from C-3' of 19 S. Yarnmoto and K. Bloch J. Biol. Chem. 1970,245 1670. 20 E. E. van Tamelen R. P. Hanzlik R. B. Clayton and A.L. Burlingame J. Amer. Chem. Soc. 1970. 92. 2137. 21 E. Caspi M.G. Kienle K. R. Varma and L. J. Mulheirn J. Amer. Chem. SOC.,1970 92 2161. 542 J. Staunton mevalonic acid. On the basis of past results it can be concluded that at the lanosterol stage this label from [2-'4C]mevalonic acid is carried by the methyl group trans to the main chain as shown. Taken together these results show that the hydrogen added to C-25 in the reduction step comes from above the plane of the paper in diagram (19). It was shown earlier that the hydrogen added at C-24 in this reduction comes from the medium to add to the lower face of the double bond in (19) so that the overall stereochemistry of addition is trans. The conversion of lanosterol to cholesterol (20) also involves the loss of both of the methyl groups attached to C-4.These groups are known to be removed sequentially by oxidation followed by release as carbon dioxide. Earlier studies on this sequence of reactions have provided indirect evidence from incorporation values to suggest that the a-methyl group is the first to be oxidised. Direct evidence to support this proposal has now been obtained22 by incubating the 4,4-dimethylsterol (21; R = Me) under aerobic conditions with a microsomal preparation depleted in NADf. Under these conditions the oxidation of the alcohol group at C-3 to a ketone is suppressed and a hydroxy-acid accumulates. When this intermediate was reincubated with the microsomes in the presence of NAD+ carbon dioxide was generated presumably by decarboxylation of the corresponding j3-keto-acid.The isolation of this intermediate hydroxy-acid provides the first direct approach to the elucidation of the order of removal of the two methyl groups. The carboxyl was assigned to the a-position as in (21 R = CO,H) but only on the basis of indirect n.m.r. evidence so that further evidence will be required to prove conclusively that the carboxy-group in the intermediate has the a-and not the j3-orientation. Indole Alkaloids.-The recent spectacular rate of progress in this field has not been maintained this year. Reference has already been made in the section on monoterpenes to the experiments which show that 10-hydroxynerol and 10-hydroxygeraniol can each serve as a precursor of loganin (6).6*7As might be expected each of these pre- cursors was also incorporated into the C-10 unit of the various indole alkaloids.5-Deoxyloganin also serves as an intermediate in loganin biosynthesis in Vinca r~sea.~~ However apart from these results very little has been discovered yet about the sequence of reaction steps leading from geraniol to loganin. 22 W. L. Miller and J. L. Gaylor J. Biol. Chem. 1970,245 5369 5375. 23 A. R. Battersby A. R. Burnett and P. G. Parsons Chem. Comm. 1970 826. Biosyn thesis 543 The very late stages of indole alkaloid biosynthesis are also unknown. It may be speculated that a compound such as (22) may serve as a late intermediate for several classes of alkaloids. A number of alkaloids having this carbon skeleton have been isolated from Rhazya plants this year but none of the compounds so far reported is considered to be a direct biosynthetic intermediate.24.25 The report which appeared last year that glycine can serve as a specific pre- cursor of the terpenoid unit of cephaline has prompted similar studies on the possible role of glycine in the biosynthesis of the corresponding unit of a number of indole alkaloid^.^^*^' In the examples tested this year only random incorpora- tion of activity was observed.The confused pattern of results in this area is probably a further reflection of the relative inaccessibility of the sites of mono- terpene synthesis in many plants. In this situation a minor metabolic pathway to a key intermediate may operate in one plant but not in another and thus produce apparently conflicting results.Ergot Alkaloids.-The ergoline system represented here by elymoclavine (24; R = OH) is known to be derived from tryptophan and mevalonic acid and chanoclavine-1 (23) has been shown to serve as an intermediate. The cyclisation to form the new ring takes place with concomitant cis,trans-isomerism about the side-chain double bond so that C-17 of (23)becomes C-7 of the ergoline skeleton. (23) (24) In current work it has been confirmed by feeding (23) labelled with tritium at C-17 that only one of the two hydrogens at this position is retained in elymo- clavine.28 The aldehyde corresponding to (23) was then prepared and was shown 24 G. A. Cordell G. F. Smith and G. N. Smith Chem.Comm. 1370 189; also R. T. Brown G. F. Smith K. S. J. Stapleford and D. A. Taylor Chem. Comm. 1970 190. 25 A. R. Battersby and A. K. Bhatnagar Chem. Comm. 1970 193. 26 D. Groger W. Maier and P. Simchen Experientia 1970 26 820. 27 J. P. Kutney J. F. Beck V. R. Nelson K. L. Stuart and A. K. Bose J. Amer. Chem. Soc. 1970 92 2174. '' B. Naidoo J. M. Cassady G. E. Blair and H. G. Floss Chem. Comm. 1970,471. 544 J. Staunton by tritium labelling to be efficiently converted to elymoclavine but now without loss of hydrogen from C-17. The aldehyde is therefore almost certainly an intermediate in the cyclisation process. The experiments described above were carried out in the intact organism but another group has prepared from CEauiceps a cell-free extract which can convert chanoclavine-1 into elymoclavine (24; R = OH).29 On the other hand agro- clavine (24; R = H) was not converted to elymoclavine in this system.This negative result is surprising in view of earlier reports of a positive conversion of agroclavine to elymoclavine in the intact organism. However a negative result in a cell-free system is significant and this result strongly suggests that agro- clavine is not a true intermediate in the cyclisation process. Now that the cell-free system is available it should be much easier to discover the mechanism of this intriguing cyclisation step. Isoguinoline Alkaloids.-Further results3* have appeared on the biosynthesis of the alkaloid erythraline (29) and all the evidence is in agreement with the scheme (25)-+ (26)+(27)j(28)-+(29).First it was shown that only the ( +)-isomer of norprotosinomenine (25) served as precursor. The diphenol (27) HO Me0 Me0 (25) (26) OH J labelled with tritium at C-3 and C-9 together with 14C in methoxy-groups was incorporated without change in isotopic ratio. By similar experiments an intact incorporation of the intermediate (28) was also demonstrated. Finally on administration of norprotosinomenine labelled with I4C in the starred methyl group erythraline was obtained with the label equally distributed between the 0-methyl and the methylenedioxy-groups. This result proves that a symmetrical '' E. 0.Ogunlana B. J. Wilson V. E. Tyler and E. Ramstad Chem. Comm. 1970 775. 'O D. H. R. Barton R.B. Boar and D. A. Widdowson J. Chem. SOC.(0,1970 1213. Biosynthesis 545 intermediate such as the diphenol (27) is produced at some stage in the bio- synthesis. The first experimental clue to the origin of the two 'extra' carbons (C-1 and C-9) of the 1-methyl isoquinoline analonidine (30; R = H) came last year with the demonstration that the C-9 methyl group incorporates activity from the methyl group of pyruvate. In a continuation of this study [l-'4C]peyoruvic acid (30; R = C02H) was administered to peyote cactus plank3' A specific incorporation into analonidine was observed and all the activity was shown to reside at C-1. In supporting experiments to show that peyoruvic acid is a true intermediate the amino-acid was detected in extracts of the peyote cactus and in addition it was found to evolve carbon dioxide when incubated with peyote slices.These results provide the first direct experimental support for Hahn's proposal that the corresponding pyruvic acid can act as the biological condensing agent in isoquinoline biosynthesis. By similar experiments it was shown that peyoxylic acid (31 R = C0,H) is probably an intermediate in the biosynthesis of anhalamine (31 R = H). It is interesting to note that the product isolated from the in vivo decarboxylation of peyoruvic acid was not anhalonidine but was the corresponding 1,2-dehydro-compound and on this basis it is possible that the decarboxylation may be an oxidative reaction. The Piperidine Alkaloids.-Lysine is known to serve as a precursor of the piper- idine nucleus of a wide range of alkaloids and it is convenient to group these compounds together irrespective of structural class.In current work on the biosynthesis of sedamine (34) it has been found that [2-3H ,6-14C]lysine (32) was incorporated into the alkaloid without change of isotopic ratio.32 This result rules out pipecolic acid (35) as intermediate and suggests that the decarboxylation precedes oxidation at C-2. All the available evidence is consistent with a biosynthesis via the aldehyde (33). 3' G. J. Kapadia G. S. Rao E. Leete M. B. E. Fayez Y. N. Vaishnav and H. M. Fales J. Arner. Chern. SOC.,1970 92 6943. 32 R. N. Gupta and I. D. Spenser Phytochernistry 1970,9 2329. 546 J. Staunton It may be speculated on the basis of structural relations that the lycopodium alkaloid cernuine (37) is derived by combination of two units of pelletierine (36); for clarity one of these units is emphasised by heavy type in (37).The theory was (36) (37) tested by administering [4-3H,6,2'-14C]pelletierine to Lycopodium plants.33 Cernuine incorporated activity without change in isotopic ratio and further evidence for an intact incorporation was sought by degradation. The surprising result then emerged that although pelletierine is incorporated intact it con- tributes only the one 'pelletierine unit' marked in heavy type in (37). Activity was also incorporated from [2-'4C]lysine. The specific site of labelling was not determined but the preliminary results of degradation were in keeping with the incorporation of two units of this precursor uiu a symmetrical intermediate.It has also been proposed that the related alkaloid lycopodine may be a modified dimer of pelletierine. In incorporation studies34 with pelletierine variously labelled with I4C and tritium evidence was again obtained for an intact incorporation. However for lycopodine as for cernuine degradation of the molecule revealed that only one unit of the precursor had been incorporated to produce the part of the molecule marked by heavy lines in (38). Thus it appears (38) that lycopodine and cernuine have a related biosynthesis from lysine and the process involves the combination of one unit of pelletierine with an unknown intermediate which in each case is probably closely similar to pelletierine in structure.The Lythraceae alkaloids represented by decodine (41)may also incorporate an intact unit of pelletierine although this possibility has not yet been tested experimentally. In current work it has been shown that lysine can serve as a precursor of ring A.35 The activity from [6-'4C]lysine (39)was equally distributed between the two marked positions so a symmetrical intermediate is involved. Multiply-labelled [~arboxyl-'~C,P-'~C]phenylalanine (40)was also incorporated 33 R. N. Gupta Y.K. Ho D. B. MacLean and I. D. Spenser Chem. Comm. 1970,409. 34 M. Castillo R. N. Gupta Y.K. Ho D. B. MacLean and I. D. Spenser J. Amer. Chem. SOC.,1970 92 1074. 35 S. H. Koo R. N. Gupta I. D. Spenser and J. T. Wrobel Chem.Comm. 1970 396. Biosynthesis 547 and the activity was shown to reside at the marked positions in diagram (41).36 The distribution of activity between C-1' and C-3' was the same as that in the I Me0 (41) precursor so that the residue comprising ring D plus this side-chain is probably derived from an intact c&3 unit. On the other hand although C-1 was active C-3 was not which suggests that ring c together with C-1 is incorporated as a C,-Cl unit (or possibly a c6&2 unit) derived from phenylalanine. These results leave C-2 C-3 and C-4 to be accounted for and it may be significant that these three carbons together with ring A have the same skeleton and oxygenation pattern as pelletierine (36). The piperidine ring of coniine (42) is not derived from lysine but on the basis of earlier results the whole carbon skeleton is known to be derived from four units 142) of acetate linked in a head-to-tail manner.[6-''C]5-Oxo-octanoic acid has now been found to serve as an efficient precursor and the corresponding aldehyde was even more effi~ient.~~,~~ Essentially all the activity from C-6 of the octanoic acid was incorporated at the corresponding position C-1' of coniine. The evidence from the incorporation experiment was complemented by dilution analysis to show that the plant produced 5-0x0-octonoic acid after the administra- tion of l-I4C octanoic acid. Pyrrolizidine Alkaloids.-The biosynthesis of the senecic acid portion (C-1 to C-7) of the alkaloid senecionine (44) has now been clarified by a more detailed study of the pattern of incorporation of activity from isoleucine (43) and threo- nine.39 Administration of [2-'4C]isoleucine to Senecio plants was followed by 36 S.H. Koo F. Comer and I. D. Spenser Chem. Comm. 1970 897. 37 E. Leete and J. 0.Olson Chem. Comm. 1970 1651. 3R E. Leete. J. Amer. Chem. SOC.,1970 92 3835. 39 D. H. G. Crout N. M. Davies E. H. Smith and D. Whitehouse Chem. Comm. 1970 635. 548 J. Staunton isolation of (44)in which the activity was shown by degradation to be equally distributed between the two carbonyl groups. When [6-'4C]isoleucine was 1 "ClO "CO I I ? I (43) o)--icH2 incorporated the methyl group attached to C-2 carried 58% of the activity. The remaining activity was not located but probably resides at C-4.These results together with the corresponding pattern of incorporation from threonine suggest that the senecic acid arises by a novel biosynthetic pathway involving the coupling of two intermediates derived from isoleucine. Amaryllidaceae Alkaloids.-The alkaloid ismine (46) has been shown to derive from oxocrinine (45)and is therefore related in biosynthesis to haemanthamine.40 Thus when oxocrinine labelled with tritium as indicated was administered to Sprekelia plants the ismine was found to be labelled with tritium at the corre- sponding positions. T T (45) (46) Po1yketides.-This year has seen some very important developments in the polyket ide field. Biichi has shown that aflatoxin B (50) incorporates activity from acetic acid to produce the intriguing labelling pattern ~hown.~' The scheme of degradation employed in this study was of exemplary thoroughness and the activity was measured directly for ten strategically placed carbons.The distribution of activity follows for the most part the alternating pattern corresponding to a polyketide biosynthesis but with two notable exceptions. There is a direct link between two carbons derived from the carboxy-group of acetate and there is also a pair of directly linked carbons derived from the methyl group. The distri- bution of activity across the labelled positions was uniform. These results are in 40 C. Fuganti and M. Mazza Chem. Comm. 1970 1466. 4' M. Biollaz G. Biichi and G. Milne J. Amer.Chem. Sac. 1970,92 1035. Biosynrhesis 549 accord with a biosynthesis from a single polyketide chain proceeding through the sequence of intermediates (47) +(48) -+(49) +(50). The scheme involves an 00 0 OH t I interesting oxidative rearrangement of ring D in (47) to form the furanofuran system of (48). Biichi has proposed for this transformation a detailed but so far unsubstantiated reaction scheme involving rearrangement of an endoperoxide intermediate. Further feeding experiments were carried out to test the ~cherne.~' For example compound (47 R = H) and the corresponding phenol (47; R = OH) labelled in each case with tritium were administered to Aspergiffusflauus but no incorporation was observed for these early precursors.On the other hand other workers4' have obtained evidence to support the later stages of the scheme. Radioactive 5-hydroxy dihydrosterigmatocystin [compound (49; R = OH) with the double bond of ring A reduced] gave a good incorporation in A. parasiticus into aflatoxin B (the corresponding dihydro derivative of alfatoxin B '). However the precursor was labelled only in the 0-methyl group and therefore further evidence will be required to establish an intact incorporation. It is interesting to compare the use of 14C as a tracer in the aflatoxin study with the use of 13C-labelling in a recently reported re-e~amination~~ of the biosynthesis of sterigmatocystin (49 R = H). [l-' 3C]Acetic acid and [2-13C]acetic acid were administered to Aspergillus versicolor and the corresponding samples of sterigmatocystin were examined by I3C n.m.r.The spectra were simplified by applying proton noise decoupling so that the signal from each isotopically labelled position appeared as a singlet. In this way the sterigmatocystin was shown to have nine carbon atoms derived from the carboxy-group of acetic acid and eight derived from the methyl group. The complete labelling pattern shown 42 G. C. Elsworthy J. S. E. Holker (Mrs.) J. M. McKeown J. B. Robinson and L. J. Mulheirn Chem. Comm. 1970 1069. '' M. Tanabe T. Hamasaki and H. Seto Chem. Comm. 1970 1539. 550 J. Staunton in structure (49)was deduced by correlating each carbon atom with a signal or a group of signals in one of the n.m.r. spectra. The assignments were based on chemical shift alone and were not confirmed independently.The pattern agrees with that suggested on the basis of an earlier in~estigation~~ using 14C as the tracer but in the 14C study it was necessary to carry out extensive degradations and even so the pattern of activity was determined directly for only five positions. In particular the determination of the complete 14C- labelling pattern of the xanthone ring would pose an especially difficult problem and it is in this type of situation that the advantage as a tracer of 3C compared with 14Cis most obvious. On the other hand it must be emphasised that the determination of the bio- synthetic origin of each carbon atom by 13C n.m.r. is only as reliable as the correlation ofthat carbon with a particular line in the spectrum.In a complicated molecule such as sterigmatocystin there will almost certainly be some degree of uncertainty in the assignment in the case of closely-spaced signals and it will usually be desirable to provide independent evidence for some of the assign- ments perhaps by measuring the spectra of suitable derivatives. Even so one can be confident that much less effort will be required to determine the 13C- as opposed to the 14C-labelling pattern. This important advantage of 13C is not of course unique to the polyketide field although clearly the greater power and convenience of the n.m.r. method is most obvious when a mqltiply-labelled compound is under investigation. As the facilities for routine measurement of 3C n.m.r.spectra are now becoming more generally available it may be expected that I3C will be used to an increasing extent in future biosynthetic work. However in assessing the relative merits of the two isotopes it must be recognised that the I3C method will only be viable when incorporation levels are relatively high and in addition when dilution with non-labelled material' can be kept within relatively low limits. These factors cannot always be con- trolled in experiments with the intact organism and it may be expected that any increase in the use of I3Cas a tracer will reinforce the trend to use cell-free systems and isolated enzymes for biosynthetic experiments. It must be emphasised that all the advantages do not lie with 13C and this can be seen by comparing two papers which have appeared this year on the biosynthesis of radicinin (51).In a 'C carboxy- and methyl-labelled acetates were administered separ- ately to the fungus Stemphyliurn rudicinum and the two samples of radicinin ;....'.,.^-" *Me (51) 44 J. S. E. Holker and L. J. Mulheirn Chem. Comm. 1968 1576. 45 M. Tanabe M. Seto and L. Johnson J. Amer. Chem. SOC.,1970,92,2157. Biosynthesis 55 1 were examined by I3C n.mr. The assignments were again based on chemical shift values and the results were interpreted in terms of the complete labelling pattern shown. In the investigation with radiocarbon the correspondingly labelled acetates were fed to the same organism and the samples were examined by degradati~n.~~ In the scheme employed it was possible to measure the activity of only 7 of the 12 carbons.The results were in agreement with the labelling pattern indicated by the n.m.r. method although the evidence was less comprehensive. [2-'4C]-Malonate was then fed to test the possibility that two separately formed poly- ketide chains are involved in the biosynthesis. It was found that each of the two methyl groups now carried only 11 % of the total activity instead of the value (16x)corresponding to a uniform distribution. Therefore the biosynthesis probably involves two separately formed chains and the two methyl groups correspond to the chain starter units. This differential incorporation of malonate could be observed with much greater confidence by the radioactive counting method than it would be by 13Cn.m.r.with present instrumentation. It seems probable therefore that the two isotopes will be used in parallel in favourable circumstances ;the radioactive isotope will be the method chosen for an experi- ment where it is important to gain an accurate measure of the distribution of activity across two or more labelled positions whereas the stable isotope will be preferred for an experiment in which it is necessary to determine only the position of labelling. Relatively few experiments with late precursors have been carried out in the polyketide field and it is therefore encouraging to see the success of several recent investigations of this type. In the case of the benzophenone sulochrin (53) the early results on the incorporation of acetate and malonate were inter- preted in terms of a biosynthesis from two separately formed polyketide chains (52) (53) and on this basis it was argued that anthraquinone intermediates were not involved.However direct evidence has now come from two groups to show that the anthraquinone questin (52) is a direct precursor of sulochrin. In the first approach questin specifically labelled with 14C in the 0-methyl group was administered to P. frequent~ns.~~ All the activity in the resulting sulochrin was shown to reside in the phenolic 0-methyl group whereas there was no activity in the carboxymethyl group which suggests an intact incorporation. This point was established with more confidence by feeding questin multiply-labelled with 46 J.F. Grove J. Chem. SOC.(c?,1970 1860. 47 S. Gatenbeck and L. Malstrom Acra Chem. Scand. 1969. 23 3493. 552 J. Stuunton I4C at the two centres indi~ated.~' The sulochrin showed an efficient incorpora- tion (18%j and was proved by degradation to carry all the activity at the expected positions with an unchanged isotopic ratio. The intermediate stages in the biosynthesis of mycophenolic acid (55) have also been investigated by feeding late precursor^.^' Earlier results have shown that the nucleus is derived from acetate ciu the polyketide pathway whereas the side-chain is derived from two units of mevalonic acid. In current work the Me Me I OH OH phthalide (54) was incorporated efficiently into mycophenolic acid but a number of related compounds were not.It can be concluded from this result that the side-chain is added after the formation of the aromatic ring. A wide range of carboxylic acids have been shown to serve as chain starters in polyketide biosynthesis but in the examples studied so far only acetate or propionate units have been found to add in the chain building steps. An investiga- tion of the origin of the ethyl groups of the antibiotic (56j has produced the Me (56) interesting result that butyric acid or a derivative may serve as a chain-building unit along with acetate and pr~pionate.'~ The compound did not incorporate activity from methionine which argues against generation of the ethyl groups by successive addition of two C-1 units as in phytosterol biosynthesis.On the other hand activity was incorporated efficiently from acetic propionic and butyric acids. The activity was not measured directly for any of the eight key carbon atoms but the preliminary results on the pattern of incorporation from the variously labelled butyric acids suggest that each of the two C,-units indi- cated by heavy type in (56),may be derived by intact incorporation of a butyrate unit. While much information about the range of building blocks which can take part in polyketide biosynthesis has been obtained from incorporation studies '' R. F. Curtis C. H. Hassall and D. R. Parry Chem. Comm. 1970 1512. 4y L. Canonica W. Kroszczynski B. M. Ranzi B. Rindone and C. Scolastico Chem. Comm. 1970 1357. J. W. Westley R.H. Evans D. L. Pruess and A. Stempel Chem. Comm. 1970 1467. Biosynthesis 553 there was until this year no direct experimental evidence on the nature of the steps leading from acetate and malonate to aromatic compounds. It is supposed that an intermediate polyketide is involved but all attempts to detect such compounds in the biological system have proved unsuccessful. It has therefore been speculated that enzyme-free intermediates might not be produced but that all the processes leading to the complete polyketide intermediate and from it to the first stable aromatic product might take place on one enzyme. The lack of success in the biological field is in marked contrast to the recent rapid developments in the synthesis of polyketides such as (57).Synthetic compounds of this type show an unexpected degree of stability but readily undergo cyclisation to form aromatic products under the appropriate conditions. For example (57)cyclises to form (58 ;R = Me) and this process parallels exactly C02 R 0 OH (57) (58) the biosynthetic scheme.” A review of the work in this field has been published this year.52 However these results are not directly relevant to the biological problem and the nature of the process by which acetate and malonate are condensed to form phenolic compounds has remained one of the great unsolved mysteries of biosynthesis. Lynen has now obtained the key to solution of this problem by isolating and purifying from the mould P. patdurn the enzyme which is responsible for the synthesis of 6-methylsalicylic acid (60) from acetyl CoA and malonyl COA.~~ Apparently only one enzyme is required to carry out the many reaction steps involved and no enzyme-free intermediates were detected.The biological reducing agent NADPH is required for the production of 6-methylsalicylic acid and when it was omitted triacetic lactone (61) accumulated instead of the resorcinol(58; R = H). This result suggests that the reduction of the keto-group to an alcohol must occur before the final malonate residue can be added to the chain and it may be speculated that an enzyme-bound intermediate such as (59) is involved rather than a true polyketide corresponding to (57). 5‘ T. T. Howarth G. P. Murphy and T. M. Harris J. Amer. Chem. SOC.,1969 91 517.52 T. Money Chem. Rev. 1970 70 553. 53 P. Dimroth M. Walter and F. Lynen European J. Biochem. 1970 13 98. 554 J. Staunton The successful purification of this enzyme is probably the most promising and exciting development in the polyketide field since Birch gave the first direct experimental support for the theory by his pioneering studies on the incorpora- tion of labelled acetates. The complexity of the overall synthesis can be appre- ciated by considering that for the conversion of acetyl CoA and malonyl CoA to 6-methylsalicylic acid at least ten different reaction steps are required and that at least six different types of reaction are employed. It is reasonable to suppose that the enzyme is a multi-functional enzyme related to that involved in fatty acid biosynthesis and it will not be surprising if further work reveals a similar mode of operation.However the biosynthesis of an intermediate such as (59) requires a greater degree of control than that involved in fatty acid bio- synthesis. Instead of carrying out a repetitive cycle of reactions following the addition of each new C-2 unit the new enzyme will need to ‘programme’ the synthesis so that the appropriate sequence of reactions is employed after each condensation step. For example in the synthesis of 6-methylsalicylic acid the active site for ketone reduction is employed only during the second condensation cycle and not during the first or the third. The enzyme capable of carrying out this complicated multistage synthesis must be of extraordinary complexity and the breakthrough in this field can be expected to lead to many further exciting developments.Miscellaneous Products.-The carbon skeleton of the fungal metabolic gliotoxin (63) is known to be assembled from phenylalanine and an aliphatic amino-acid possibly serine. Evidence has now been obtained that the rneta-tyrosine does not serve as an intermediate. The gliotoxin derived from phenylalanine fully (63) CHzoH deuteriated in the aromatic ring was shown by mass spectrometry to have retained all five deuterium atoms.54 Dehydrogenation of ring A was accompanied by the loss of two deuteriums from the 2H5-species. A later paper described the feeding of phenylalanine labelled with tritium in the rneta-p~sition.~~ In this case the carbinol carbon of ring A was shown by degradation to carry 50 % of the tritium incorporated into gliotoxin.These results interlock convincingly to suggest that rn-tyrosine is not an intermediate but that the biosynthesis involves cyclisation of the nitrogen atom on to the epoxide ring in an intermediate such as (62). The phenazines are known to incorporate activity from shikimic acid but little is known about the intervening steps. Pyocyanin (64; R = OH) has now 54 J. D. Bu’Lock and A. P. Ryles Chem. Comm. 1970 1404. 55 N. Johns and G. W. Kirby Chem. Comm. 1971 163. Biosynthesis 555 been shown56 to derive from the intermediate (64 R = C02H). When the tetradeuterio-compound was incorporated all four deuterium atoms were Me I ? R D (64) retained in the ring c of pyocyanin.These results suggest that the conversion involves a direct oxidation decarboxylation. Ho2cq -+ f eI I p " \ Me OH 0 (65) (66) The quinone ring of plastoquinone-9 (66) incorporates activity from homo-gentisic acid (65).57 Evidence for a specific incorporation into (66) came from feeding experiments with homogentisic acid specifically labelled with 14C on the or-position as indicated but the degradation scheme did not show which of the two methyl groups carried the activity. Administration of the precursor uniformly labelled with I4C produced a labelling pattern consistent with in- corporation of an intact C6-C,unit. 0 0 (67) In the case of lawsone (67) it is probable on the basis of earlier evidence that shikimic acid provides all the carbons of ring A together with one of the carbons of ring B.The origin of the remaining three carbons was obscure but it has now been discovered that glutamic acid serves as a specific precursor.58 It was proved by degradation that all the activity from [l-14C]glutamate was located at either C-1 or C-4. The enzyme which catalyses the cyclisation of the chalcone (68) to the flavone (69) has been isolated from Mung bean seedlings.59 After t!:? reaction was 56 M. E. Flood R. B. Herbert and F. G. Holliman Chem. Comm. 1970 1514. 57 G. R. Whistance and D. R. Threlfall Biochrm. J. 1970 117 593. 58 I. M. Campbell Tetrahedron Letters 1969 4777. 59 K. Hahlbrock H. Zilg and H.Griseback European J. Biochem. 1970 15 13. 556 J. Staunton (68) (69) carried out in deuterium oxide the resident hydrogen on the a-carbon of the chalcone was shown by n.m.r. to have adopted the equatorial (p)orientation in the product so the overall stereochemistry of the addition is trans. OMe OMe I (72) dibityl (73) Ribityl The [OMe-'4C]isoflavone (70) is converted into amorphigenin (71) by ger- minating seedlings of A. fruticosa6' All the activity was shown by degradation to reside in the fragment C-6 plus C-6a and therefore almost certainly at C-6. The flavone was proved to be a natural metabolite of A. fruticosa by dilution analysis after administration of [l-l4C]pheny1alanine. This experiment estab- lishes the first direct link between the 2'-methoxyisoflavanoids and the rotenoids.The biosynthesis of riboflavin (73) involves an interesting reaction between two molecules of lumazine (72). One molecule of the precursor contributes a C,-unit (corresponding to the two methyl groups together with C-6 and C-7) which is condensed with the methyl groups of the second molecule to generate ring c of the product. The direction of incorporation of the C,-unit into riboflavin has been shown to be the same for both the enzymic6'*62 and the chemical reaction,63 by deuterium labelling and n.m.r. The two methyl groups do not become equivalent during transfer but the group on C-6 of the precursor provides the methyl on C-7 in riboflavin and vice versa. On the basis of this and other evidence a detailed mechanism has been proposed for the reaction in both systems.'' L. Crombie P. M. Dewick and D. A. Whiting Chem. Comm. 1970 1469. G. W. E. Plaut R. L. Beach and T. Aogaichi Biochemistry 1970,9 760 771. 62 R. L. Beach and G. W. E. Plaut J. Amer. Chem. Soc. 1970,92 2913. 63 T. Paterson and H. C. S. Wood Chem. Comm. 1969,290.

ISSN:0069-3030    

DOI:10.1039/OC9706700535

出版商:RSC    

年代:1970

数据来源: RSC

摘要:

18 Enzyme Mechanisms By M.AKHTAR and D. C. WILTON Department of Physiology and Biochemistry University of Southampton SO9 5NH THElast Report on Enzyme Mechanisms in 1968 dealt with reactions involving the hydrolysis of peptide and glycosidic linkages. The present review deals with the mechanism* of action of enzymes requiring the participation of coenzymes such as pyridine nucleotides and 5’-deoxyadenosyl-B 2 and of a newly discovered group of ‘modified amino-acid’ prosthetic groups. Since Annual Reports (B)are directed primarily towards readers interested in organic chemistry we have confined ourselves to the selection of material which is relevant to the ‘bio- organic’ aspect of the enzyme mechanisms. We apologize in advance to those authors whose work has been omitted either due to the limitation of space or over- sight on our part.1 Basis of Enzyme Catalysis Intramolecular reactions involving compounds in which the ground-state structure resembles the geometry of the transition state show spectacular reacti- vity when compared to their intermolecular counterparts. Thus a major contribu- tion to the efficiency of biological reactions may be made by bringing together the substrate molecules and the catalytic groups at the active site of the enzyme in the perfect arrangement for the given reaction to occur. This concept has been the basis of instruction in enzyme mechanisms at many institutions for several years. The universal acceptance of this view was hindered by the assertion of Koshland and co-workers who calculated that the contribution of proximity and proper orientation of the substrates to the rate of enhancement could not satis- factorily explain the efficiency of enzymes.’ The latter position has now been modified2 and the revised view accepting the importance of ‘proper orientation’ of substrates in enzymic reactions has received wide publicity3 on the basis of experiments carried out on model systems2 and given the title ‘Orbital Steering’.It has been shown2 that the acid-catalysed esterification of (2)is about lo6 times faster than the bimolecular reaction between methyl alcohol and acetic acid and about 1.3 x lo4 times faster than the lactonization of (1). Bruice and co-workers ’ D. E. Koshland and K. E. Neet Ann. Rev. Biochem. 1968 37 359.* D. R. Storm and D. E. Koshland Proc. Nat. Acad. Sci. U.S.A. 1970,66,445. Chem. in Brit. 1970,6 372 and 551 ; Chem. Eng. News July 1970 54. * The term mechanism in the present context refers to the bond-forming events which ensue after the formation of the enzyme-substrate complex (ES). M. Akhtar and D. C. Wilton had previously shown4 that the intramolecular reaction of the monophenyl ester of dicarboxylic acid anion (4) was about 5 x lo4times faster than the analogous reaction with (3). This study has recently been e~tended.~ In another report6 the lactonization of (6)has been found to be 2.5 x lo7times faster than that of (5). The obvious explanation for the dramatic rate enhancement in compounds (2) (4) and (6)is the juxtaposition of the reacting atoms in the ground-state structure so that the transition state for the reaction is reached with a minimal loss of trans- lational entropy.These studies highlight the contribution made to rate enhance- ment by the presence of reactive centres in an intramolecular environment and further emphasise the stringent geometrical requirement that must be fulfilled to achieve the maximal reactivity. It may be noted that these features are already well recognized in the literature and form the basis of several methods used in structure determination and selective syntheses. 2 Coenzyme-B, The biosynthesis of vitamin-B ,has been recently reviewed.' Coenzyme-B (7) (also called cobamide coenzyme or 5'-deoxyadenosyl-B Jis formed enzymically * from vitamin-B 2 a reducing agent and ATP (Scheme 1).A non-enzymic syn- thesis of the coenzyme has also been reported.' The participation of coenzyme- B, has been demonstrated for several enzymes and these are discussed below. Reviews" and a monograph' covering this and related aspects are available. Dio1dehydrase.-This enzyme catalyses the conversion of both the (R)-and (9-enantiomorphs of propanediol into propionaldehyde and also of ethylene glycol 'T. C. Bruice and U. K. Pandit J. Amer. Chem. SOC. 1960,82 5858. ' T. C. Bruice and A. Turner J. Amer. Chem. SOC. 1970,92 3422. ' S. Milstien and L. A. Cohen Proc. Nut. Acad. Sci. U.S.A. 1970,67 1143. H. C. Friedmann and L. M. Cagen Ann. Rev. Microbiol. 1970 24 159. A. Peterkofsky and H. Weissbach Ann.New York Acud. Sci. 1964 112 622; G. A. Walker S. Murphy and F. M. Huennekens Arch. Biochem. Biophys. 1969 134 95. A. W. Johnson L. Mervyn N. Shaw and E. L. Smith J. Chem. SOC. 1963,4146. lo (a)H. P. C. Hogenkamp Ann. Rev. Biochem. 1968,37,225;(b)H. A. Barker Biochem. J. 1967,105 I ;(c)T. C.Stadtman Ann. Rev. Microbiof. 1967,21 121 ;(d)F. Wagner, Ann. Rev. Biochem. 1966 35 405. E. L. Smith 'Vitamin-B I l'r Methuen's Monographs on Biochemical Subjects London 1965. Enzyme Mechanisms n B" g.j-f/oy 2e co -+ cb' -+ co HO OH HO OH Coenzyme-B Vitamin-B Vitamin-B 2s ATP "CH2-Rib-I KO) Scheme I X = Triphosphate (7) into acetaldehyde.12 The reaction proceeds with the transfer of one of the C-1 hydrogen atoms of propanediol to C-2 without exchange with protons of the medium.' Using (R)-propanediol it is the HRthat migrates to C-2 (8a)-+ (9a); however the hydrogen atom with the opposite stereochemistry H, is involved when (S)-propanediol is the substrate (8b) -+(9b).14 The displacement of the 2-position hydroxy-group in both the isomers occurs with inversion of configura-ti~n.'~.'~ It has been suggested that conformations of the two isomers at the enzyme surface as shown in structures (8a) and (8b) permit the observed steric course.' With respect to the status of oxygen atoms in the dioldehydrase reac- tion it has been shown that in the conversion of (R)-propanediol into propion- aldehyde the oxygen atom originally present at C-1 is lost and is replaced by the oxygen from C-2 (8a)-+(9a).On the other hand in the conversion of (S)-propanediol the C-1 oxygen atom is retained in the product (8b)-+(9b).16 These experiments have been rationalized by assuming the intermediacy of the gem-diol(22) followed by stereospecific dehydration.16 Me H H. A. Lee and R. H. Abeles J. Biol. Chem. 1963 238 2367. l3 A. M. Brownstein and R. H. Abeles J. Biol.Chem. 1961,236 1199. l4 B. Zagalak P. A. Frey G. L. Karabatsos and R. H. Abeles J. Biof. Chem. 1966,241 3028. l5 J. Retey A. Umani-Ronchi and D. Arigoni Experienriu 1966 22 72. l6 J. Retey A. Umani-Ronchi J. Seibel and D. Arigoni Experientiu 1966,22 502. 560 M. Akhtar and D.C.Wilton A contribution to the understanding of the mechanism of action of coenzyme- B, linked enzymic reactions was made by the demonstration that when a mixture of [l-3H,]propanediol and unlabelled ethylene glycol was incubated with dioldehydrase both the products propionaldehyde and acetaldehyde contained tritium in the a-position.” Analogous results were obtained in the conversion of a mixture of [l-2H,]propanediol and propanediol when mono- deuterio-propionaldehyde was the main product.’ These results highlighted for the first time that hydrogen transfer from C-1 to C-2 in these reactions was not strictly intramolecular. Furthermore the incubation of [l-3H,]propanediol and unlabelled coenzyme-B, with the enzyme resulted in the incorporation of tritium at C-5’ of the adenosyl moiety of the recovered coenzyme.” These results suggested that in the dioldehydrase reaction the hydrogen atom from C-1 is transferred to C-2 cia the coenzyme.This was confirmed by showing that chemically synthesised coenzyme-B containing tritium at C-5’ transferred tritium to the product when added to the enzyme and unlabelled s~bstrate.’~ Glycerol Dehydrase.-This enzyme catalyses the conversion2’ of glycerol to P-hydroxypropionaldehyde ;however mechanistic studies of the type described above for the dioldehydrase have not yet been reported. Ethanol Deaminase.-This enzyme has been isolated as a homogenous protein and catalyses the conversion of ethanolamine (10)into acetaldehyde.21.22 In this reaction one of the hydrogen atoms from the carbinol carbon atoms is trans- ferred to the amino carbon atom without exchange with water,23 the alcohol C-atom becomes the carbonyl C-atom of acetaldehydeZZb and the oxygen atom of the substrate is retained in the product.23 When [5’-3H,]coenzyme-Bl is used in the enzymic reaction the isotopic hydrogen is transferred to the a-position of a~etaldehyde,~ thus suggesting mechanistic similarity between the dioldehydrase and ethanolamine deaminase reaction.Ribonucleotide Reductase. 5-In the three enzymic reactions discussed above the reaction centres of the substrate undergoing oxidation and reduction were part of the same molecule. An interesting variation on this theme is provided by R. H. Abeles and B. Zagalak J. Biol. Chem. 1966 241 1245. Is J. Retey and D. Arigoni Experientia 1966 22 783. l9 P. A. Frey M. K. Essenberg and R.H. Abeles J. Biol. Chem. 1967 242 5369. 2o Z. Schneider E. G. Larsen G. Jacobson B. C. Johnson and J. Pawelkiewicz J. Bid. Chem. 1970 245 3388. ’‘ C. Bradbeer J. Biol. Chem. 1965 240 4675. 22 (a)B. H. Kaplan and E. R. Stadtman J. Biol. Chem. 1968,243,1787;(b)B. H. Kaplan and E. R. Stadtman J. Biol. Chem. 1968,243 1794. ” B. M. Babior J. Biol. Chem. 1969 244 449. 24 Unpublished work quoted in Ref. 23. ’’ The literature on this enzyme is reviewed in Ref. 10a and by R. L. Blakley and E. Vitols Ann. Rev. Biochem. 1968 37 201. Enzyme Mechanisms 561 the enzyme ribonucleotide reductase which catalyses the coenzyme-B depend-ent reduction of ribonucleotide triphosphates (1 1) into the corresponding de- oxyribonucleotide triphosphates (12).This reaction compulsorily requires the oxidation of one mole of a dithiol per mole of ribonucleotide reduced.26 In the conversion (1 1) -+ (12) the new hydrogen atom at C-2’ of ribose is derived from the medium2’ and the overall reaction occurs with the retention of con- figuration.28 Reduction of [Z-’ 80]adenosine triphosphate to deoxyATP results in complete loss of the isotope from the nucleotide whereas [3’-180]ATP is reduced to [3’-180]deoxyATP with the same isotopic content.28c When the ribonucleotide reductase reaction is carried out in the presence of tritiated water the recovered coenzyme-B contains tritium at the S-position.*’ These results have been rationalized as shown in Scheme 2 involving the reduction of the coenzyme by dithiol followed by the displacement of the C-2’ hydroxy-group of the substrate by a hydride from the reduced coenzyme29 (see also Scheme 3).The exchange of the 5’-hydrogens of the coenzyme with the protons of the medium has also been observed in a partial reaction without the substrate ribonucleotide triphosphate but in the presence of allosteric activator^.^^' * S-H + Coenzyme F El + Coenzyme.*H + *Hf Is-; + Coenzyme-H* -+ x - ~ o ~ sCoenzyme ~ HOx-cQBase OH HO H* (11) (12) Scheme2 X = Triphosphate Methylmalonyl CoA Mutaw.-This enzyme catalyses the interconversion of (R)-methylmalonyl CoA (L-methylmalonyl CoA) and succinyl CoA (13a) (14a). The reaction involves the counter transfer of a hydrogen atom and the carbonyl thioester group and occurs without exchange with the protons of the medium.30 The retention of configuration during the conversion (13a) -+( 14a) was established by using the deuterio-analogue (13).The resulting succinyl CoA 26 E. Vitols and R. L. Blakley Biochem. Biophys. Res. Comm. 1965 21 466. ’7 M. M. Gottesman and W. S. Beck Biochem. Biophys. Res. Comm. 1966,24,353; R. L. Blakley R. K. Ghambeer T. J. Batterham and C. Brownson Biochem. Biophys. Res. Comm. 1966,24,418. ” (a) A. Larsson Biochemistry 1965,4 1984; (b)T. J. Batterham R. K. Ghambeer R. L. Blakley and C. Brownson Biochemistry 1967 6 1203; (c) H. Follmann and H. P. C. Hogenkamp Biochemistry 1969,8,4372. ” (a) W. S. Beck R. H. Abeles and W. G. Robinson Biochem. Biophys. Res. Comm. 1966 25 421; (b) R. H. Abeles and W.S. Beck J. Biol. Chem. 1967 242 3589; (c) H. P. C. Hogenkamp R. K. Ghambeer C. Brownson R. L. Blakley and E. Vitols J. Biol. Chem. 1968 243 799. 30 Literature on this aspect is covered in Ref. 10a and by J. W. Cornforth and G. Ryback Ann. Reports 1965 62 428. M. Akhtar and D.C. Wilton (14) on hydrolysis yielded (S)-monodeuteriosuccinic acid (15)? The use of [5’-3H,Jcoenzyme-Bl in the mutase reaction resulted in the incorporation of tritium into (13a) and (14a).’*~~~ Me D 27 HO2C CO-SCOA HO2C H H02C H (13)(13a) D =H CH( NH 2)C02H / CH H ->; + H02C CH(NH2)C02H HO,C D HO2C D (16) (17) (18) (16a) D =H (17a) D =H Glutamate Mutaw.-This enzyme catalyses the reversible conversion of L-glutamate (17a) to threo-/?-methyl-L-aspartate(16a).The enzymic reaction in- volves the counter transfer of a glycine moiety and a hydrogen atom.’Ob When the deuteriated analogue (16) was used in the enzymic reaction and the resulting glutamic acid (17) degraded (R)-monodeuteriosuccinic acid (18) was ~btained.~ This suggested that the conversion (16) -+(17) occurs with the inversion of c~nfiguration.~~ The involvement of 5’-hydrogen atoms of coenzyme-B in the glutamate mutase reaction has been claimed. lob L-fl-Lysine Mutase-This enzyme catalyses the reversible conversion of L-p-lysine (19) to 3,5-diaminohexanoate (20).34 Two other related enzymes3 participate in the interconversions of D-a-lysine (19a) 2,5-diaminohexanoate (20a) and L-ornithine (19b)*2,4-diaminopentanoic acid (20b).These transfor- mations involve the counter transfer of a hydrogen atom and an amino-group which in the case of the L-P-lysine mutase reaction occurs without exchange with the amino-group of free ammonia34a or the hydrogen of water.36 When the L-p-lysine mutase reaction is carried out in the presence of [5’-3H,]coenzyme-B,2 the tritium is transferred to C-6 of 3,Sdiaminohexanoate (20) and to C-5 of L-/3-lysine (19)?’ Another analogous enzymic interconversion of L-lysine and L-/?-lysine surprisingly does not involve3’ the participation of coenzyme-B12. 3’ M. Sprecher M. J. Clark and D. B. Sprinson J. Bid. Chem. 1966 241 872. 32 G. J. Cardinale and R. H. Abeles Biochim. Biophys. Actu 1967 132. 517. ” M. Sprecher R. L. Switzer and D. B. Sprinson J.Biol. Chem. 1966,241 864. 34 (a)R. C. Bray and T. C. Stadtman J. Biol. Chem. 1968,243,381; (b)E. E. Dekker and H. A. Barker J. Biol. Chem. 1968,243 3232. 35 (a)T. C. Stadtman and L. Tsai Biochem. Biophys. Res. Comm. 1967,28,920; (6)J. K. Dyer and R. N. Costilow J. Bacteriul. 1970,101,77 (c)Y.Tsuda and H. C. Friedmann J. Biol. Chem. 1970 245 5914. 36 J. Retey F. Kunz T. C. Stadtman and D. Arigoni Experientia 1969 25 801. 37 T. C. Chirpich V. Zappia R. N. Costilow and H. R. Barker J. Biol. Chem. 1970 245 1778. Enzyme Mechanisms R-CH,-CH,-NH R-CH(NH,)-Me (19 19a 19b) (20 20a 20b) (19) and (20) R = H0,C-CH2-CH(NH,)- (19a) and (20a) R = HOzC-CH(NH,)-(CH2)2-(19b) and (20b) R = HO,C-CH(NHJ-CH,-Mechanism.-The cumulative evidence presented suggests that in the above transformations coenzyme-B, acts as a hydrogen carrier'3*'4*' 'and that during the course of the enzymic reactions one of the hydrogen atoms of the substrate molecules and both the C-5' hydrogen atoms of the coenzyme become enzymic- ally indistingui~hable.~~~*~ 8,39 This could be achieved through the transfer of a hydride ion or its equivalent from the substrate to the coenzyme thus resulting in the formation of a C-5' methyl group and a reduced cobalt species (21).29'*38 This mode of cleavage of the carbon-cobalt bond was originally deduced38 by considering the formal reversal of the process involved in the biosynthesis of the coenzyme (Scheme I).The re-formation of the coenzyme (7) from the reduced species (21) may then occur through a number of closely related processes.The suggested me~hanisrn~~.~' for the dioldehydrase reaction is outlined in an H 1 5' / -C -H Scheme 3 H CO-SCOA CO.SCoA H (7) + (13a) (21) + +S.H H*q (7) + (14a) [H C02H H C02 H I (231 (24) abbreviated form in Scheme 3 and may be adopted for glycerol dehydrase ethanolamine deaminase and ribonucleotide reductase reactions. In the case of the last enzyme the reduced coenzyme (21) is formed by the reaction:2gc (7) + dithiol e(21) + disulphide. A similar mechanism for the methylmalonyl -'8 M. Akhtar Comp. Biochem. Physiof. 1969 28 1. 39 A mechanism similar to that in Scheme 3 appears to have been considered by R. H. Abeles and R. Williams Abstracts of 8th International Congress of Biochemistry Switzerland 1970 p.135. 564 M. Akhtar and D.C. Wilton CoA mutase reaction has been proposed38 and briefly it involves the formation of a carbonium ion intermediate (23) which after rearrangement to (24) followed by reduction with (21) yields the product. That the methyl intermediate as in structure (21) may participate in the coenzyme-B ,dependent reactions was originally suggested by the important observation that in the dioldehydrase reaction the use of a pseudo-substrate capable of supporting only the initial reaction (corresponding to the first reaction of Scheme 3) resulted in the formation of 5'-deo~yadenosine.~' Similar results were later obtained with ethanolamine deamina~e.~~ Another type of mechanism has also been considered involving a homolytic process for the cleavage of the carbon-cobalt bond42 of (7) followed -Rib-&2 -Rib-kH2 / / H ./ (C'iI) ;-+H-C-+ -Rib-C-H + C-\ \ \ (25) (26) by a hydrogen-atom transfer to give (25) and (26).42" This principle,42a when generally extended to coenzyme-B ,dependent enzymic reactions will require in several cases radical species to undergo unorthodox rearrangements displace- ments or eliminations to furnish products.On the other hand a heterolytic cleavage of the carbon-cobalt bond can rationalize not only the mechanisms of the coenzyme-B, dependent enzymes but also that of methyl-B, linked meth- ionine bio~ynthesis.~~.~~ However a clear choice between the two types of mechanism cannot be made at present.It is conceivable that the final solution may incorporate features from both types of mechanism. Vitamin-B also participates in the biosynthesis of methionine methane and acetic acid. In these reactions methyl-B ,[-(Co)-Me] is the crucial intermediate This aspect of the situation has been reviewed,"" up to 1968. 3 Modified Amino-acids as Prosthetic Groups It has recently come to light that the traditional r61e of pyridoxal phosphate in some enzymic reactions is performed by modified amino-acid residues. Histidine decarboxylases catalyse the decarboxylation of hystidine to yield histamine (29) and CO . One such enzyme from Lactobacillus 30a contains covalently bound pyruvate as the prosthetic group (27).44 It has been suggested that the carbonyl group of the pyruvyl residue forms a Schiff base (28) with the substrate which 'O 0.W.Wagner H. A. Lee P. A. Frey and R. H. Abeles J. Biol. Chem. 1966,241 1751. '' B. M. Babior J. Biol. Chem. 1970 245 1755. 42 (a)B. M. Babior J. Biol. Chem. 1970 245 6125; (b) M. A. Foster H. A. 0.Hill and R.J. P. Williams in 'Biochemical Society Symposia No. 31 ;Chemical Reactivity and Biological Role of Functional Groups in Enzymes' ed. R. M. S. Smellie Academic Press London 1970. 43 R. T. Taylor and H. Weissbach Arch. Biochem. Biophys. 1969 129 728 745. 44 W. D. Riley and E. E. Snell Biochemistry 1968 7 3520; P. A. Recsei and E. E. Snell Biochemistry 1970 9,1492. Enzyme Mechanisms facilitates decarboxylation. Biosynthetic experiments suggest that the pyruvyl residue in histidine decarboxylase originates by the modification of a serine m~iety.~’ A pyruvyl residue has also been shown to be involved in the analogous conversion catalysed by S-adenosyl-methionine decarb~xylase.~~ Amino-acid H Me + I I CH,-C-C-NH-protein -+ R-C-N-C--+ $ 03rotein R-CHz-NHz + (27) 00 (29) I1 II €-I-i \o A R=N+ ,NH (27) (28) C D-Proline reductase which catalyses the conversion of proline into 5-aminovaleric acid in the presence of a dithiol also contains a pyruvyl prosthetic gro~p.~’ A hypothetical mechanism for the conversion has been ~uggested.~’ a-Ketobutyrate has been identified as the prosthetic group of urocanase (30)which catalyses the hydration of urocanate to give (32).48 A mechanism of reaction involving the intermediacy of (31) which permits an attack of OH-at position 4 has been ~uggested.~’ Urocanic acid + Et -C -NH I1 I100 -Protein -+ N 7CH=CH-COzH -C-C-NH- f’rotein (30) r( J 0 Histidine and phenylalanine ammonia lyases catalyse the reaction (33)+(34).In the case of the histidine ammonia lyase reaction the elimination involves the removal of H from the p-carbon atom.49 The inacti~ation~~-’~ of these enzymes with NaB3H4 followed by acid hydrolysis of the protein led to the isolation of radioactive alanine containing most but not all of the tritium in the p-po~ition.~~-”These results have been interpreted in terms of the presence of a dehydroalanyl residue in the enzymes and the partial structure (35) for the active site has been propo~ed,4~3~~ though no evidence for the existence of >C=N-45 W.D. Riley and E. E. Snell Biochemistry 1970,9 1485. 46 R. W. Wickner C. W. Tabor and H. Tabor J. Biol. Chem. 1970,245,2132. 4’ D. Hodgins and R. H. Abeles J. Biol. Chem. 1967,242,5158; Arch. Biochem. Biophys. 1969 130,274. O8 D. J. George and A. T. Phillips J. Biol. Chem. 1970 245 528. 4y I. L. Givot T. A. Smith and R. H. Abeles J. Biol. Chem. 1969 244 6341 ;J. Retey H. Feirz and W. P. Zeylemaker F.E.B.S.Letters 1970,6 203. 50 R. B. Wickner J. Biol. Chem. 1969 244,6550. 51 K. R. Hanson and E. A. Havir Arch. Biochem. Biophys. 1970,141 1. M. Akhtar and D.C. Wilton linkage [encircled in (35)Jis at present available. A mechanism of action for the enzymic reactions has been proposed.This involves the addition of the amino- group of the substrate (33) to the p-carbon atom of the dehydroalanyl residue followed by an elimination reaction and finally the regeneration of the enzyme in several steps.51 An alternative formulation of the active site compatible with the available evidence is shown in structure (36)which allows the enzymic reaction to occur via (37) in two steps. CO,HI R-CH2-CH(NH,)+ R-CH=CH-CO,H + PjH (33) (34) + (33) -+ (35) Protein Protein (36) R I 1 -(34) + (36) (37) 4 Pyridine Nucleotides A large group of enzymes catalyse the general reaction involving the transfer of a hydrogen between the coenzyme and substrate. The enzymes taking part in the \ I C=X + NAD(P)H* + H+ H*-C-X-H + NAD(P)’ / I usually reversible reactions where X is oxygen and nitrogen are called dehydro- genases and have been the subject of recent excellent reviewsand discussion^.^^-^ However the pyridine nucleotide linked saturation of carbon double bonds has yet to be shown to be reversible and the enzymes are termed reductases.Conformation of Pyridine Nucleotides-The three-dimensional structure of pyri -dine nucleotides in solution has recently been subjected to critical evaluation using 220 MHz n.m.r.56 Although the pyridine ring of reduced pyridine nucleotides is planar,57 n.m.r. data reveal that the two hydrogens at C-4 are non-equivalent. 52 A. Frankfater and I. Fridovich Biochem. Biophys. Acta 1970,206,457. 53 S. P. Colowick J.van Eys and J. H. Park in ‘Comprehensive Biochemistry’ ed. M. Florkin and E. H. Stotz Elsevier Amsterdam 1966. 54 H. Sund in ’Biological Oxidations’ ed. T. P. Singer Interscience New York 1968. ‘Pyridine Nucleotide Dependent Dehydrogenases’ ed. H. Sund Springer-Verlag Berlin 1970. 56 R. S.Sarma and N. 0. Kaplan Biochemistry 1970,9 539 549 557. 57 I. L. Karle Acta Crvst. 1961 14 497. Enzyme Mechanisms 567 This non-equivalence is due to interaction of the adenine and nicotine rings which results from two possible folded conformations P and M of the pyridine nucleotide with the intermediacy of an open-chain form. If folded conformations u M-HELIX P-HELIX are relevant to the enzyme mechanism then the coenzyme should be bound to the A and B specific dehydrogenases in the M and P helices respectively.Fluorescence studies suggest that alcohol lactic glutamic and glycerol-3-phosphate dehydro- genases bind the coenzyme in the open config~ration.~~ Only glyceraldehyde-3- phosphate dehydrogenase appears to bind in the closed config~ration.~~ The recent 220 MHz n.m.r. data on the binding of NADH to lactic dehydrogenase suggest a closed configuration for the coenzyme ;59 however these observations are inconsistent with the 2.8 X-ray crystallographic structure.60 Structure of Dehydrogenases.-In the past few years rapid advances have been made in the elucidation of the structure of dehydrogenases. These advances have included the amino-acid sequence of glyceraldehyde-3-phosphatedehydrogen-ase,6 liver alcohol dehydrogenase,62 and glutamic dehydr~genase.~~ The 2.8 8 three-dimensional X-ray structure of lactic dehydrogenase has now been deter- mined.60 At the time of writing neither the amino-acid sequence nor the high- resolution X-ray structure of the same dehydrogenase were yet available.Active Site Groups.-Sulphur amino-acids. Elucidation of mechanisms for a group of enzymes is facilitated if unifying features within the group are discovered (cj serine proteases). Similarities do exist between certain dehydrogenases in particular with respect to the ‘essential thiol peptide’. Treatment of nine species of ” S. F. Velick ‘Light and Life’ ed. W. D. McElroy and B. Glass Johns Hopkins Balti- more 1961. ‘9 R. S. Sarma and N. 0.Kaplan Proc.Nut. Acad. Sci. U.S.A. 1970,67 1375. 6o M. J. Adams G. C. Ford R. Koekoek P. J. Lentz A. McPherson M. G. Rossmann I. E. Smiley R. W. Schevitz and A. J. Wonacott Nature 1970 227 1098. 61 B. E. Davidson M. Sajgo H. F. Noller and J. I. Harris Nature 1967 216 1181 ;J. I. Harris and R. N. Perham ibid. 1968 219 1025. 62 H. Jornvall European J. Biochem. 1970 16 25. 63 E. L. Smith M. Landon D. Piszkiewicz W. J. Brattin T. L. Langley and M. D. Melamed Proc. Nut. Arad. Sci. U.S.A. 1970 67 724. M. Akhtar and D. C. Wilton glyceraldehyde-3-phosphatedehydr~genase~~ and also yeast and liver alcohol dehydrogena~e~’ with iodoacetate resulted in the and lactic dehydrogena~e~~.~~ inactivation of the enzymic activity and selective hydrolysis of the alkylated proteins furnished peptide fragments which contained carboxymethylated cyste- ine.Possible similarities of amino-acids between the ‘essential thiol peptides’ of the enzymes have been but as yet it is not possible to draw any general conclusion regarding the common genetic origin of or mechanistic function for amino-acids in the various fragments. In the case of lactic dehydrogenase the cysteine may be required for the binding of the substrate but not of the coenzyme.68 Iodoacetate inactivated cytoplasmic malate dehydrogenase through the alkyla- tion of a methionine4’ (cf. mitochondria1 enzyme below). Lysine. Inactivation of glutamic dehydrogenase with 4-iodoacetamido-salicylic acid involves the alkylation of a ~ysteine~’.~’ Incubation of as well as a ly~ine.~’ the enzyme with the inhibitor in the presence of a-oxoglutarate protects the enzyme from inactivation and results in the alkylation of cysteine but not of lysine.This result indicates the important r61e of a lysine in the binding of substrate. The lysine also reacts with a number of other reagents and has been identified as lysine 93 and the amino-acid sequence around it determined.63 A similar sequence surrounds lysine 212 of glyceraldehyde-3-phosphatedehydro-genase.61 A mechanistic r61e for lysine has also been suggested for lactic dehydr~genase~’ Attention is drawn to recent and alcohol dehydr~genase.~~ work in which it has been shown that the modification of the amino-group(s) (presumably c-amino-groups of lysine) of alcohol dehydrogenase with (38) resulted in a dramatic increase in the enzymic 0 II 0C-CH2Br 64 R.N. Perham and J. I. Harris J. Mol. Biol. 1963,7 3 16; W. S. Allison and J. I. Harris Abstracts 2nd F.E.B.S. Meeting 1965 p. 140. 65 J. 1. Harris Nature 1964 203 30. 66 T. P. Fondy J. Everse G. A. Driscoll F. Castillo F. E. Stolzenbach and N. 0.Kaplan J. Biol. Chem. 1965 240 421 9. 67 J. J. Holbrook G. Pfleiderer K. Mella M. Volz W. Leskovac and R. Jeckel European J. Biochem. 1967 1 476. 68 J. J. Holbrook and R. A. Stinson Biochem. J. 1970,120 289. 69 V. Leskovac and G. Pfleiderer 2.physiol. Chem. 1969,350,484. 70 A. D. B. Malcolm and G. K. Radda European J. Biochem. 1970 15 555. ’’ J. J. Holbrook P. A. Roberts B. Robson and R. A. Stinson in ‘Abstracts of 8th International Congress of Biochemistry’ 1970 p.83. 72 A. D. Winer and G. W. Schwert J. Bid. Chem. 1958,231 1065; 1959,234 11 55. 73 E. M. Kosower ‘Molecular Biochemistry’ McGraw-Hill New York 1962. 74 B. V. Plapp J. Biol. Chem. 1970 245 1727. Enzyme Mechunisms 569 Histidine. The inactivation of lactic dehydrogenase with (39) involves the alkyla- tion of a cysteine in the essential thiol peptide and also a hi~tidine.'~ A histidine has also been directly demonstrated to be at the active site of mitochondria1 malate dehydr~genase.~~ Less direct evidence for the involvement of a histidine has been obtained in the case of rabbit muscle cytoplasmic a-glycerol phosphate dehydrogenase.77 Histidines have long been implicated in mechanisms for dehydrogenases.Winer and Schwert proposed histidine as the proton source during reduction in the case of a lactic dehydr~genase~~ while Ringold has presented a general mech- anism for dehydrogenases involving a histidine residue. This mechanism allows for the activation of both substrate and coenzyme by a hi~tidine.~~ Tryptophan. The role of tryptophan at the active site of dehydrogenases is at present under debate. Schellenberg has shown that incubation of both yeast alcohol dehydr~genase~~ and lactic dehydrogenase" with tritiated substrate I (3H-C-OH) in the presence of NAD at high pH resulted in the incorporation I of tritium into the protein. The label was shown to be located in the methylene group ofa tryptophan to which has been assigned a mechanistic r61e.Attempts to confirm the work using liver alcohol dehydrogenase,62 glyceraldehyde-3-phos- phate dehydrogenase,8 malate dehydrogenase,82 and lactic dehydrogenase7 1*7 have been unsuccessful. Using yeast alcohol dehydrogenase Palm83 has shown a time-dependent incorporation of radioactivity in the protein not only from [l-3H]ethanol but also from [4B-3H]NADH (this enzyme utilises the A side). Of possible pertinence in this connection is the observation that non-enzymic tritium exchange may be observed between NAD and NADH as a result of complex formation.84 Similar interactions between NAD+ and tryptophan were facili- tated at high pH.85 Although no direct tritium exchange has been observed in the latter case it would seem reasonable that the specialised environment of the enzyme surface coupled with the non-ionised nature of tryptophan at high pH might well produce such an exchange.Thus Schellenberg's observation could reflect the interaction of the coenzyme and tryptophan at the active site. Trypto- phan has already been implicated as being in close proximity to the coenzyme at the active site of dehydrogenases as the result of fluorescence and inactivation studies. *v8 75 V. C. Woenckhaus J. Berghauser and G. Pfleiderer 2.physiol. Chem. 1969,350,473. 76 B. H. Anderton European J. Biochem. 1970 15 562. 77 R. Apitz-Castro and Z. Suarez Biochirn. Biophys. Acra 1970 198 176. " H. J. Ringold Nature 1966 210 535. 79 K. A. Schellenberg J. Biof. Chem. 1965 240 1165; 1966 241,2446.'O K. A. Schellenberg J. Biol. Chem. 1967 242 1815. " W. S. Allison M. J. Connors and D. J. Parker Biochem. Biophys. Res. Comm. 1969 34 503. 82 L. M. Allen and R. G. Wolfe Biochem. Biophys. Res. Comm. 1970,41 1518. '' D. Palm Biochem. Biophys. Res. Comm. 1966,22 151. 84 J. Ludowieg and A. Levy Biochemistry 1964,3 373. 85 G. G. A. Alivisatos F. Ungar A. Jibril and G. A. Mourkides Biochirn. Biophys. Acta 1961,51 361. '6 P. L. Luisi and R. Favilla European J. Biochem. 1970 17 91. M. Akhtar and D.C. Wilton Metal Ions.-Zinc is associated with some dehydrogenases. In the case of the liver alcohol dehydrogenase this metal can be replaced by Co2+ or CdZ+ without any appreciable loss of enzymic a~tivity.~’ Mechanisms involving Zn2 + have been propo~ed~~,’~,~~ for dehydrogenases but lack experimental verification.Geometry of the Active Site.4ther highlights in the study of the active site of dehydrogenases include the use of a spin-labelled analogue (40) of NAD.89*90 This analogue in which the N-O bond has been suggested to correspond to the C-N bond between the nicotinamide and the ribose of NAD binds to liver alcohol dehydrogenase and is competitive with NADH.89 The n.m.r. proton relaxation times of either ethanol acetaldehyde or isobutyramide when bound to the enzyme in the presence of (40) have been used to establish the spatial geometry of the substrate and coenzyme at the active site. With each compound the oxygen atom occupies the same point in space relative to the c~enzyme.’~ In addition e.s.r.studies provide evidence that the substrate binds to form a ternary complex on the solvent side of the coenzyme.89 The nature of the binding site of the 3a-steroid dehydrogenase from Pseudo-rnonus testosteroni has been subjected to a rigorous investigation.” This work has shown how the enzyme becomes more specific and efficient as the substrate used changes from cyclohexanone up through substituted two- and three-ringed ketones to the normal steroid nucleus. Finally Eisele and Wallenfels have observed stereoselective inactivation of certain dehydrogenases using the two antipodes of a-iodopropionic acid and OL-iod~propionamide.~’ A-specific dehydrogenases are more rapidly inhibited by the D-an tipode whereas the L-antipode is more effective against B-specific enzymes.This correlation must reflect the nature of the coenzyme binding site on the enzyme as in the tentative Scheme shown ~pposite.’~ The Order of Bond Formation During the Reduction of C=C.-The mechanism of pyridine-nucleotide-linked reduction of C=C has been extensively studied. These reductions may be divided into two types depending upon whether or not the olefin linkage is conjugated to an electron-withdrawing group. In the enzymic ” D. E. Drum and B. L. Vallee Biochem. Biophys. Res. Comm. 1970,41,33. N. Evans and B. R. Rabin European J. Biochem. 1968,4 548. 89 A. S. Mildvan and H. Weiner Biochemistry 1969 8 552. 90 A. S. Mildvan and H. Weiner J. Biol. Chem. 1969 244 2465. 91 H. J. Ringold J.M. H. Graves A. Clark and T. Bellas Recent Prugr. Hormone Res. 1967 23 349. 92 K. Wallenfels and B. Eisele European J. Biochem. 1968 3 267; B. Eisele and K. Wallenfels in ‘Pyridine Nucleotide Dependent Dehydrogenases’ ed. H. Sund Springer- Verlag Berlin 1970. Enzyme Mechanisms A enzyme + B enzyme + A enzyme + B enzyme + coenzyme coenzyme D(+)a-iodo-L(-)qr-i?do-propionic acid proplonlc acid or amide or amide (R = 0- NH2) (R = 0; NHZ) reduction of conjugated ketones a hydrogen from the medium always adds at the position CY to the carbonyl while the hydrogen from the pyridine nucleotide is transferred to the p po~ition.~~,'~' From cofactor 1 1 H \/ Ill c=c -+-C-C-C-/a fl\ I1 I I -C OH II T 0 From medium Examples of double bonds not conjugated to electron-withdrawing groups are found during the biosynthesis of cholesterol from lanosterol and occur at the A7.8 A14.15 7 3 and ~24.25positions.The complete stereochemistry and orienta- tion of addition of hydrogens to these double bonds has now been determined and in each case the orientation of addition is consistent with a Markownikoff mechanism. Protonation of the double bond occurs first to give the most stable carbonium ion which is subsequently neutralised by the addition of a hydride ion from the coenzyme.94 Thus activation of the substrate in the reduction of C=C is achieved by an enzyme-mediated protonation step and the coenzyme simply completes the process initiated by the enzyme. Because of the formal similarity between all pyridine nucleotide linked reduc- tions it is possible to draw a general mechanism (Scheme 4) in which activation Enz.(H+) Enz.I,,+ NAD(P>\ ,TD(P),+ \ H-C-X-H /C-x-H I Scheme 4 93 J. S. McGuire and G. M. Tomkins Fed. Pror.. 1960 19 A-29; 0. Berseus and I. Bjorkhem Europeun J. Biochenr. 1967 2 503; D. C. Wilton and H. J. Ringold Proc. 3rd Int. Congr. Endocrinology 1968 no. 263; I. Bjorkhem European J. Biuchern 1969 8 345;J. D. Robinson R. 0.Brady and C. R. Maxwell J. Lipid Res. 1962 3 243. 94 D. C. Wilton K. A. Munday S. J. M. Skinner and M. Akhtar. Biochem. J. 1968 106. 803; M. Akhtar K. A. Munday A. D. Rahimtula I. A. Watkinson and D. C. Wilton Chem. Comni. 1969 1287; 1. A. Watkinson D. C. Wilton K. A.Munday and M. Akhtar Eiochern. J. 1971 121 131. 572 M. Akhtar and D. C. Wilton of the substrate is the crucial first step. Support for this mechanism is provided by evidence resulting from the study of model chemical systems. This work has been discussed by a number of a~thors~~,~~ and therefore it is our intention only to summarise the general conclusions that may be drawn. Dihydropyrjdine compounds have been used with only limited success for the reduction of non-activated double-bond species. However compounds contain- ing activated double bonds such as Malachite green (41)9”and riboflavin (42),”’ CH,OH I Ph are rapidly reduced at room temperature. Furthermore it is interesting to note that riboflavin is much more rapidly reduced under acid conditions due to initial protonation of the riboflavin facilitating hydride transfer.97 These obser- vations re-emphasise the requirement for protonation of the substrate prior to hydride transfer in pyridine nucleotide reductions as proposed above for C=C reductions.Pyridine Nucleotides in Carbohydrate Transformations.-UDP-D-glucose 4‘-epimerase catalyses the NAD linked reaction UDP-D-glucose (43) UDP-D-+ galactose (49 involving the inversion of the hydroxy-group at C-4. The reaction proceeds without incorporation of hydrogen or oxygen from the solvent98 while a hydrogen isotope effect is observed when UDP-[4-3H]-~-glucose is used.99 The mechanism shown in (43) -+(44) +(45) involving the intermediacy of enzyme- bound NADH and UDP-4-oxo-~-glucose has been proposed for this reaction.98 Recent observations using an equal mixture of perdeuteriated and non-deuteriated (43)have established that the hydrogen transfer at C-4 is intramolecular and uses CHzOH CHzOH CH20H Em.-NAD’ +HO (or) ]eNA:4y3.u1 0-UDP-[.*y+r) 0-UDP OH OH OH (43) (44) (45) 95 T.C. Bruice and J. Benkovic ‘Bio-organic Mechanisms’ vol. 11 Benjamin New York 1966; K. A. Schellenberg in ‘Pyridine Nucleotide Dependent Dehydrogenases’ ed. H. Sund Springer-Verlag. Berlin I970 ;K. Wallenfels ibid. 96 D. H. Mauzerall and F. H. Westheimer J. Amer. Chem. SOC., 1955,77,2261. 97 C. H. Suelter and D. E. Metzler Biochim. Biophys. Acfa. 1960,44,23. 98 I. A. Rose Ann. Rev. Biochem. 1966,35 23. 99 S. Kirkwood and G. L.Nelsestuen Biochim. Biophys. Acta 1970 220 633. Enzyme Mechanisms (Y!*UDP +[ H(-T-UDP CH20H HO (46) NHAc NADH 0 NHAc + Enz.-NAD J + CHzOH CH OH (LqH +UDj -3 OH HN HO NADH .o NAD+ (47) only one face of NADH.'" A related mechanism is involved in the conversion (46)-+(47).lo I Glucose-6-phosphate-myo-inositol-1-phosphate cyclase catalyses the NAD' linked cyclisation (48) --* (50). This reaction occurs without re- arrangement of the carbon skeleton and with retention of configuration at each carbon atom."' By double-labelling techniques C-1 C-3 and C-5 hydrogen atoms were shown to be retained during the cycli~ation,'~~ whereas one of the two hydrogen atoms at C-6 is lost.'03*'04 The r61e of a 5-0x0 intermediate (49) has been suggested on the basis of an isotope effect observed with the C-5 tritiated substrate.lo3 UDP-D-glucuronic acid decarboxylase catalyses the conversion of CH20@ .O (q--+ IDH$fF -NADH p v H HO OH HO HO OH OH OH ~ (48) (49) + 1 Enz.-NAD+ OH (50) UDP-D-glucuronic acid (51) into UDP-D-xylose (54).In the reaction (51)+ (54) the hydrogen atoms at C-3 C-4 and C-5 of the substrate are retained. The conversion of the 4-tritiated analogue (51) is attended by a significant isotope loo L. Glaser and L. Ward Biochim. Biophys. Actu. 1970 198 613. 'O' W. L. Salo and H. G. Fletcher Biochemistry 1970,9 882. lo' F. Eisenberg A. H. Bolden and F. A. Loewus Biochern. Biophys. Res. Comm. 1964 14,419; I. W. Chen and F. C. Charalampous J.Biol. Chem. 1965,240,3507; H. Kindi J. Biedl-Neubacher and 0.Hoffman-Ostenhoff Z. physiol. Chem. 1965,341 157. J. E. G. Barnett and D. L. Corina Biochem. J. 1968,108 125. Io4 I. W. Chen and F. C. Charalampous Biochim. Biophys. Acfu 1967 136 568. M. Akhtar and D.C. Wilton C02H CO2H OH (51) + Enz.-NAD + NADHo$-> 1- OH "*D+$!q) O*UDP HO 0* UDP OH OH (53) (54) effect which has been attributed to reversible oxidation at C-4 to facilitate de- carbo~ylation.'~~ Compound (52) has also been implicated in the biosynthesis of apiose. O6 Pyridine nucleotides are involved in the conversion of TDP-D-glucose (55) into TDP-4-oxo-6-deoxyglucose(56).'O7 This reaction involves the transfer of a hydrogen from C-4 to C-6 while a hydrogen from the medium is incorporated at C-5.Incubation of [4'-3H]-TDP-6-deoxyglucose with the enzyme resulted in transfer of tritium to bound NAD+ giving [4B-3H]NADH. It is this 4B tritium that is transferred intramolecularly to the C-6 position of the sugar.'07d Similar mechanisms seem to be involved in the removal of the 6-OH group during the bio- synthesis of cytidine diphosphate 3,6-dioxy-~-glucose. O8 CHZOH CH,OH HO O.TDP (q O*TDP -lADHo+q) OH OH (55) J + Enz.-NA D + OH OH (56) lo' J. S. Schutzbach and D. S. Feingold J. Biol. Chem. 1970 245 2476. H. Grisebach and V. Dobereiner Biochem. Biophys. Res. Comm. 1964 17 737. lo' (a)A. Melo W. H. Elliott and L. Glaser J. Biol. Chem. 1968,243 1467; (b)0.Gabriel and L. Lingquist J. Biol.Chem. 1968 243 1479; (c) H. Zarkowsky and L. Glaser J. Biol. Chem. 1969,244,4750; (d)S. F. Wang and 0.Gabriel J. Biol. Chem. 1970,245,8. lo* H. Pape and J. E. Strominger J. Biol. Chem. 1969 244 3598.

ISSN:0069-3030    

DOI:10.1039/OC9706700557

出版商:RSC    

年代:1970

数据来源: RSC

摘要:

ER RATA Vol. 66 B 1969 Page 261. Ref. 139,for N. L. Pau read H.-L. Pan. Page 438. Line 6 for p-halocarbonyl red a-halocarbonyl. Page 480. Formulae (49) and (50) should have dotted and full circles as shown below /------- Page 484. The ethyl group on formula (67) is misplaced the formula should appear Page 489. Formula (91)should have a dotted circle as shown below &----. \ 1‘ Me \ 0 (91) The sentence beginning on line 8 should be modified to read ‘Alkaloid L-23 from the same plant is stereoisomeric with lycodoline (92) at C-12 and nitrogen; because of the ring stereostructure (92) is held in the correct orientation to allow a-coupled overlap in the N-C-CC :0 system.81’

ISSN:0069-3030    

DOI:10.1039/OC9706700575

出版商:RSC    

年代:1970

数据来源: RSC

摘要:

AUTHOR INDEX Aaronson M. J. 12. Abbolito C. 99. Abbot G. G. 528. Abdulla Y.H. 522. Abdullah A. A. 136. Abdurahman N. 483. Abe T. 289. Abel E. W. 273 299. Abeles R. H. 495 559 560 561 562 563 564 565. Abelson J. N. 511. Aberhart J. 14. Aberlin M. E. 88. Abley P. 16 532. Aboul-Seoud A. 91. Abraham A. 432. Abraham D. J. 62. Abrahams C. 43. Abraitys V. Y. 205. Abramovitch R. A. 174 175 180 337. Abronin I. A. 19. Achenbach H. 349. Achilladelis B. 538. Achiwa K. 253 410. Achmatowicz O. 358. Acklin W. 536. Acree S. F. 130. Acton E. M. 495. Acton N. 38 I. Adamic K. 26 35. Adams C. H. M. 367. Adams G. E. 207 208 209 215 217 218. Adams J. 266 375. Adams J. M. 490 514. Adams J.Q. 27. Adams M. J. 497 567. Adams P. M. 538. Adams R. F. 25. Adam R. N. 224,227. Adams W. J. 368. Adamson D. 418. Adamson G. W. 304. Adamson R. 507. Adelstein G. 428. Adesnik M. 511. Adesogan E. K. 423. Adevik G. 34. Adhikary S. P. 419. Adickes H. W. 459. Adman E. 501. Adolf W. 41 7. Advani B. G. 444 459. Afonso A. 416. Agami C. 269,273,278. Agarwal K. L. 490. Agosta W. C. 161 195. Agranat I. 347. Agwada V. 15. Ahlberg P. 101 105. Ahlgren G. 341 342. Ahmad M. 91. Ahmad M. S. 246. Ahmad N. 286. Ahmann G. 478. Ahmed F. R. 61. Ahsan A. M. 480. Ainsworth E. W. 3 13. Ajo M. M. 148. Akagi K. 436. Akahori Y.,32. Akasaki Y. 170. Akermark B. 341. Akhtar M. 563 571. Akhtar M.H. 170. Akiba K. 304. Akiba K.-Y. 392. Akiyama K. 427. Akkerman 0.S. 328. Alam S. N. 494. Al-Baldawi S. A, 25. Albizzati E. 310. Albonico S. M. 432. Albrecht H. P. 495. Albrecht P. 43 1. Albro P. W. 523. Alcaide A. 423. Alder R. W. 447. Alekseeva L. M. 330. Alexander E. 122. Alexander R. 300. Alexandre C. 257 375. Alford J. R. 114. Alhadeff E. S.,188. A1 Holly M. M. 348. Alivisatos G. G. A. 569. Allbutt A. D. 386. Allcock H. R. 52. Allen A. O. 210 21 1. Allen D. W. 86. Allen F. H. 57 61. Allen G. R. 157 158,400 437. Allen G. W. 87. Allen L. E. 259 324. Allen L. M. 569. Allenmark S. 90. Allewell N. M. 496. Allinger N. L. 13 129. Allison A. J. 413. Allison W. S.568 569. Allred A. L. 272. Allred E. L. 121 448. Alper H. 324. Altenburger E. R. 526. Altland H. W. 250 288 529. Altman J. 398. Altman L. J. 357. Altman S. 511. Altona C. 368 373. Amar-Nacash Cl. 53 1. Amaya J. 512. Amendola M. 262. Amiet G. 280 325. Amit B. 205. Amith C. 366. Ammon H. L. 61. Amouroux R. 263 278. Amy J. W. 7 10 11. Anand R. C. 410. Anastassiou A. G. 162 174 340 463. An Bang Wu. 277. Anbar M. 207 21 1. Andersen K. K. 275 344. Anderson C. M. 158. Anderson D. G. 274. Anderson E. 73 74. Anderson J. D. 220. Anderson J. E. 191 369 373. Anderson J. M. 189 248. Anderson L. B. 233 463. Anderson N. H. 23 242. Anderson P. H. 352. Anderson R. J. 264 528.Anderson W. F. 518. Anderton B. H. 569. Andrejevic V. 190. Andrews A. T. de B. 428. Andrist A. H. 169 372 392 393. Andrulis P. J. 191. Aneja R. 55,485,529,530. Anet F. A. L. 398. Angelo B. 245. Angyal S. J. 13 366. Anisimov K. N. 325. Anner G.. 427. Ansell G. B. 49 50. Ansell M. F. 529. Anselme J.-P. 175 460. Anselmi C. 403. Antheunis D. 327. Anthonsen T. 414 423. Anthony G. M. 429. Antipin L. M. 287. Antonello C. 503. Aogaichi T. 556. Aota K. 56 407. Apeloig Y. 126 128. Apgar J. 498. Apirion D. 518. Apitz-Castro R. 569. Aplin R. T. 10 12. Appel H. H. 468. Applequist D. E. 122. ApSimon J. W. 416 426. Araki M. 407. Arase A. 284. Aratani T. 368. Archer D.A. 252 375. Arderegg J. W. 509. Arigoni D. 406 536 559 560 562. Armand J. 233. Armbrecht F. M. jun. 290. Armer B. 306. Armstrong K. I. 90. Armstrong M. C. H. 167. Armstrong R. C. 215. Arndt F. 449. Arndt R. R. 478. Arnett D. C. 64. Arnett E. M. 63 102. Arnold D. R. 205. Arnold R. A. 252 528. Arnold Z. 526. Arnott R. C. 277. Arnott S. 490 506. Arnoux J. 525. Arotsky J. 94 267. Arsenault G. P. 14. Artaud J. 230. Arth G. E. 429. Arthur A. R. J. 342. Arthur J. C. jun. 28. Asaka Y. 406. Asao T. 347. Ash D. K. 268. Ashby E. C. 277,278,279 287. Ashe A. J. tert. 165. Askani R. 160 163 316 390 400. Aso C. 71. Asofsky R. 507. Aspinall G. O. 452. Asselineau C. P. 524. Asselineau J.524 53 1. Ast W. 317. Astrakhanov M. I. 312. Atavin A. S. 152. Atidia M. 127. Atkins K. E. 319 321. Atkins P. W. 23. Atkins R. L. 264. Atkins T. J. 274. Atkinson M. R. 490. Atkinson R. F. 439. Atlas V. V. 3 16. Attea M. 107. Attridge C. J. 272 280 297. Atwell W. H. 295. Atwood J. L. 287. Aubort J. D. 78 79. Auda H. 468. Audette R. C. S. 478. Audisio G. 40. Augustine R. L. 241 311 314. Aumann R. 309 329. Avigad G. 41. Aviv H. 517. Awad B. M. 70. Axelrod E. H. 264. Axen U. 526. Axenrod T. 14. Ayer W. A. 478. Aynehchi Y. 423. Ayres D. C. 339. Ayrey G. 100. Aziz S. 79. Azuma I. 531. Babad E. 398. Babior B. M. 560 564. Babler J. H. 253 285. Bachman G.B. 190. Back T. G. 268. Bacur A. 361. Baczynski E. 530. Baczynskyj L. 14 473. Baddow F. G. 70. Baddeley G. V. 419. Badiello R. 21 5. Badley E. M. 308. Baechler R. D. 302. Baer E. 530. Baer H. H. 452. Baev A. A. 510. Bagal L. I. 135. Bagga M. M. 321. Bailes J. 33. Bailey D. M. 243. A uthor Index Bailey D. S. 252 369. Bailey D. T. 464 477. Bailey E. J. 267 429. Bailey G. C. 316. Bains M. S. 28. Baiocchi L. 11 1. Bairamov R. B. 305. Baird M. S. 381. Baitinger W. E. 7 10 11. Baizer M. M. 177 220 234. Bajdala H. 205. Bajzer W. X. 335. Baker A. J. 221 374. Baker D. J. 314. Baker L. M. 250. Baker R. 361,428. Baker R. F. 518. Baker R. T. K. 381. Baker T. J. 361. Baklan V.F. 387. Baksshi-Zade A. M. 316. Bakuzis P. 19 379. Balaban A. T. 49 367. Balaspiri L. 96. Balasubramanian A. 205. Baldwin J. E. 139 154 164 167 169 179 367 372 392 393 395 424. Baldwin S. W. 422 424. Bales S. E. 31. Baliga B. T. 107. Balkenhol W. G. 40 459. Ball D. H. 452. Ballard D. H. 291. Ballenegger M. 115. Ballester M. 101 135 338. Balls D. M. 121. Balmain A. 417 418. Balsley R. B. 94 330. Baltimore D. 489. Banciu M. 361. Bancroft K. C. C. 95 97. Bandoli G. 301. Bangerter B. W. 506. Bank S. 263. Banks C. M. 409 410. Bansal K. M. 21 1. Banthorpe D. V. 90 330 406 537. Banucci E. 446. Barak H. 240. Barakat H. 529. Barbarak J. C. 105. Barbier M. 423. Barbieri G.310. Bgrbulescu N. 35. Barcza S. 428. Bard A. J. 2 1,3 1,222,224 239. A uthor Index Baretta A. 370 373. Barfield M. 19. Barili P. L. 403. Barker H. A. 558 562. Barker H. R. 562. Barlett P. D. 440. Barlow M. 506. Barlow M. C. 317. Barltrop J. A. 200. Barnes J. D. 33. Barnes M. 131. Barnett B. L. 43 44. Barnett J. E. G. 573. Barnett L. 508 51 1. Barnett R. E. 74. Barnett W. E. 360. Baron W. J. 173. Barratt M. D. 529. Barrau J. 294. Barrell B. G. 490 508 510. Barrett E. K. 50. Bart. J. C. J. 52 301 304. Bartak D. E. 33 233. Bartell L. S. 368. Bartels A. P. 408. Barth G. 41. Bartlett E. H. 330. Bartlett L. 37 39. Bartlett P. A. 268. Bartlett P. D. 154 155 177 188 204 247 389 436.Bartlett W. R. 252. Bartley J. P.,421. Barton D. H. R. 15 162 246 248 251 254 368 421 422 424 430 474 544. Barton J. W. 330. Barton T. J. 157. Bartsch R. A. 143. Baru R. 129. Basak S. P. 479. Bassindale A. R. 280 295 330. Bassler T. 126 128. Bastani B. 355. Basters J. 35. Basu H. 530. Bates R. B. 60. 135 168. Batich C. 317 401. Batra S. 472. Batten P.L. 421. Batterham T. J.. 561. Battersby A. R. 484 536. 542 543. Battiste M. A. 31 109 119 158. Bauer S. H. 368 372 373. Bauer W. 521 Baukov Yu. I. 295. Bauld N. L. 31 340. Baum A. A. 196. Baum K. 96. Baumann W. J. 533. Baumgarten R. J. 379. Bautz E. K. 522. Bautz E. F. K. 521 522.Bautz F. A. 522. Baxendale D. 406 537. Baxendale J. H. 208 21 1 212. Baxter C. S. 162 354. Bayer H. O. 160. Bayev A. A. 51 I. Bayne W. F. 149 160. Beach R. G. 277. Beach R. L. 556. Beak P. 428. Beal D. A. 267. Beall R. 61. Bear C. A. 59. Beard C. D. 293. Beardsley K. 510. Beaud G. 5 17. Beaudreau G. S. 515. Beaulieu D. J. 491. Beaumond D. 2 1 1. Beauregard Y. 288. Beck A. K. 35. Beck F. 220. Beck G. 448. Beck H. J. 307. Beck J. F. 543. Beck R. M. 509. Beck W. S. 561. Becker K. 1 i2. Beckwith A. L. J. 190. Beckwith J. 490 522. Beddoes R. L. 309. Bedenbaugh A. O. 262. Bedenbaugh J. H. 262. Bednarczyk D. J. 528. Beecham A. F. 40. Beeman W. N. 509. Beer R. J. S. 51 449.Begland R. W. 132. Begley M. J. 479. Begum A. 20. Behoman E. J. 84. Behre H. 452. Behzadi A. 209. Beisler J. A. 480. Bell. K. H. 243. Bell R. A.. 328. Bell R. P.,138. Bell T. N. 284. Bellas T. 570. Belluco U. 308 324. Belovsk C?. 232. Belskey I. 455. Beltrame P. 100 126 128. Beltrame P. L. 128. Bemporad P. 99. Benati L. 182. Bender C. F. 172. Bender C. O. 341. Benedetti E. 44 322. Ben-Efraim D. A. 317 401. Ben-Hur E. 202 502. Ben-Ishai R. 502 503. Benjamin B. M. 117. Benkeser R. A. 232 236 244 290. Benkovic J. 572. Benkovic S.J. 87. Bennett J. E. 18 26 177. Bennett S. W. 20 294. Benschop H. P. 302. Ben-Shoshan R. 267 333. Benson R. C. 372. Bentley M. D. 106 110.Bentley P.H. 529. Bentley R. 539. Bentley R. K. 409. Berardelli M. L. 240. Bercaw J. E. 313. Beresford P. 348. Berezovskii V. M. 441. Berg H. 161 275. Berger J. 492. Berger M. N. 318. Bergeron R. 330. Berghauser J. 569. Bergin W. A. 262. Bergman E. 98 339. Bergman R. G. 121 128 174 386. Bergmann E. D. 349. Berliner E. 72 92. Berliner L. J. 49. Berman H. M. 57. Bernard M. 369. Bernasconi C. F. 99 100. Bernasek S. L. 11. Berngruber O. 31 1. Beronius P. 130. Berry D. J. 333. Berry J. W. 526. Berseus O. 571. Berson J. A. 153 154 165 204 394 395. Bertholet J. P. 425. Berti G. 403 418. Bertini F. 178 251 277. Bertorello H. E. 341. Bertrand M. 123,390,392 406. Bertrand M.P.,22 34. Bervelt J. P. 370. Berwick M. A, 187. Berwin H. J. 107. Bessard J. 227. Bestmann H.-J. 304. Bethell D. 172. Bethke H. 14. Bevan C. W. L. 100. Beverwijk C. D. M. 306. Bewick A. 235. Beyer H. 457. Beynon J. H. 7 10 11. Bezaquet A. 392. Bhacca N. S. 163 391. Bhaduri S. 518. Bhalerao U. T. 410. Bhalla V. K. 55 485. Bhamidipaty K. 427. Bhanot 0. S. 498. Bhat V. V. 228. Bhatia M. S. 410 41 1. Bhatnagar A. K. 424,484 543. Bhattacharya S. K. 149. Bhattacharyya S. C. 407. Bhereur M. 288. Biale G. 141. Biallis M. J. 84. Bianchi M. 322. Biedl-Neubacher J. 5 73. Biekelhaupt F. 263. Biellmann J. F. 418. Bielski B. H. J. 210. Biemann K. 14 17. Bienvenue-Goetz E.148. Biffin M. E. C. 98. Biger S. 241. Biggs A. G. 63. Bigon Z. 148. Biherwolf T. E. 97. Bikelhaupt F. 278. Billeter M. A. 490 515. Billups W. E. 248. Bingham R. C. 106 11 I 121. Biollaz M. 548. Biran C. 289. Birch A. J. 244 376 411. Birchall J. M. 182 341. Bird C. W. 345. Bird P. H. 55 480. Birkenmeyer R. D. 246. Birladeanu L. 164 393 429. Birnbaum G. I. 54. Birnbaum K. B. 54 485. Bischof P. 367. Bixon M. 371. Bjorkhem I. 528 571. Black D. St. C. 164. Black R. M. 191 387. Blackburn E. V. 199. Blackburn G. M. 76 498 500. Blackstock D. J. 331. Author Index Blagoev B. 272. Bolden A. H. 573. Blagoeva I. 72. Boldt P. 359. Blaha K. 40. Bollen A. 512. Blair G. E. 543.Bollinger J. M. 103. Blair J. A. 244. Bollinger S. M. 103. Blake C. C. F. 57. Bolton J. R. 18,24,26,30, Blake R. D. 57 509. 31. Blakley R. L. 560 561. Bolton P. D. 63 64. Blanchard H. S. 93. Bombieri G. 324. Blanchard K. R. 365. Bonati F. 281 308 399. Blankespoor R. 22. Bone J. A. 11 1. Blas G. S. 531. Blaschke H. 352. Bonner T. G. 90. Blattmann P. 535. Bonnett R. 441. Blazer T. A. 13. Bonnier J. M. 182. Blazevich J. N. 121. Boocock G. 318. Blecha Z. 419. Booth H. 367. Bopp R. J. 148. Bleck W. E. 309 354. Blessington B. 16. Borch R. F. 243. Bleyman M. 5 11. Borden W. T. 376 381. Blier J. E. 171. Bordwell F. G. 69 136 Blindheim U. 317. 140 142 385. Bloch K. 541. Borg D. C. 442. Blomberg C. 278. Borgen G. 37 I. Bloodworth A.J. 280 Borges del Castillo J. 467. 282. Borgwardt U. 209. Bloom A. 50. Borisov A. E. 281. Bloomfield J. J. 398. Borisov S. N. 271. Blount H. N. 227. Born M. 3 17. Blount J. F. 41. Borrell P. 200. Bortolozzo G. 301. Blow D. M. 57. Boschi T. 308 324. Bluhm A. L. 23 35. Boschung A. F. 112. Blum J. 241 267 314 Bose A. K. 14 438 543. 323. Bose K. K. 518. Bly R. S. 110. Boshagen H. 448. Blythin D. J. 201. Bosnich B. 305. Boag J. W. 209. Bossy J. M. 213. Boar R. B. 15 422,474 Botta L. 406. 544. Bottini A. T. 385. Bobbitt J. M. 227. Bottino F. 328. Bobst A. M. 505. Bottom R. 94. Boche G. 134 168. Boue S. 199. Bock H. 32. Boul A. D. 428. Bodor N. 365,492. Boulton J. J. K. 98 339. Boekelheide V. 251 351 Bourgeois P.255. 352 464. Bourgeois S. 521. Boelhouwer C. 316. Bourguignon P. 425. Bonnemann H. 313. Bourne A. J. 295. Boer F. P. 45 320 402. Bourns A. N. 142 143. Boersma M. A. M. 165 Boustang K. M. 268. 398. Boustany K. S. 268 278. Boerwinkel F. P. 149. Bowden K. 63 65 71 97 135 147. Boettiger D. 515. Bowen L. H. 305. Bogard T. L. 477. Bowers K. W. 33 245. Bogdanowicz M. J. 376. Bowers W. S. 528. Bohlmann F. 14. Bowie J. H. 9 11. Bohn R. K. 372. Bowie R. A. 197 283. Boire B. A. 155. Bowles A. J. 20 280. Bokanov A. I. 300. Bowman D. F. 26. Bolan J. 478. Bowman N. S. 101 328. Author Index Bowman R. M. 198,469. Boyd D. R. 205,436. Boyd G. V. 445. Boyd R. H. 365. Boyd S. D. 266. Boyle J. M. 504. Boyle W.S. 136. Bozik J. E. 320. Braea G. 323. Bradbeer C. 560. Bradley C. H. 329. Bradley D. F. 500. Bradshaw T. K. 9 11. Brady D. G. 325. Brady R. O. 571. Brady W. T. 157 388. Brandle R. 24. Brandange S. 468. Brandl F. 41 7. Brandt R. 14. Brannigan L. H. 67 152. Brass H. J. 84. Brattin W. J. 567. Brauer D. J. 286. Brauman J. I. 168 192. Braun P. B. 62. Bravo P. 258. Bray R. C. 562. Brehn E. 285. Breil H. 323 378. Bremer H. 504. Brener L. 376. Brennan J. P. 283. Brennan M. E. 247. Brennan P. J. 524. Brennan T. 291. Brennan T. F. 60. Brenner M. 174. Brenner S. 135 168 291 508. Breslow R. 101 138 139 226,232,344,346,424. Bretelle D. 238. Breton J. L. 467. Brettle R.222 249. Brewer C. F. 493. Brewer J. P. N. 182 341. Brewis S. 56. Brienne M. J. 41 403. Briggs L. H. 421. Briggs P. J. 83. Brignell P. J. 94. Brill. T. B. 305. Brimacombe J. S. 452. Brinich J. M. 103. Brinkmann A. W. 360 367. Brintzinger H. H. 313. Brisse F. 54 55. Brittain M. J. 182. Broaddus C. D. 264. Broadhurst M. J. 441. Brocksom T. J. 252 528. Brod L. H. 73. Broadbeck U.,493. Brois S. J. 175 433. Brorner W. M. 501. Bronskill M. J. 207. Bronstert B. 202. Bronstoff S. W. 510. Brook A. G. 274. Brook P. R. 384 388. Brookes P. R. 325. Brookhart M. 115. Brooks C. J. W. 407 429. Broom A. D. 492. Brophy G. C. 90. Brophy J. J. 375. Brossi A. 472 477. Brotherton R. J. 272.Brouwer D. M. 94 102 103. Brown A. 164. Brown C. A. 242. Brown C. K. 31 1 322. Brown D. J. 456. Brown D. M. 26 493. Brown H. C. 110,117,143 146 150 243 244 255 256 260 265 283 284 285 384 385. Brown I. 90. Brown J. C. 414. Brown J. M. 138,169,329 397. Brown J. N. 52. Brown K. C. 143. Brown M. J. 498. Brown N. M. 90 Brown P. 11 14 431. Brown P. M. 188. Brown R. D. 102. Brown R. F. C. 338. Brown R. S. 125. Brown R. T. 483 484 543. Brown S. H. 5.36. Brown W. G. 193. Browne L. M. 478. Browning H. L.,Jun. 35. Brownson C. 561. Brownstein A. M. 559. Broxton T. J. 181 338. Bruce M. I. 313 360. Bruice T. C. 71 74 75 77 132 138 150 151 454 558 572. Brumby S. 27. Brune H.A. 307. Bruni P. 22 31. Bruning W. H. 24. Bruno F. 219. Bruschweiler F. 430,43 1. Bruun T. 423. Bryan R. F. 169 417 485. Bryant M. J 317. Bryant W. F. 282. Bryce-Smith D. 96 196 197. Bryrd J. E. 72. Brzechffa M. 363. Bubb W. A. 248. Buchachenko A. L. 19. Buchanan. B. G. 17. Buchanan I. C. 23. Buchanan J. G. St. C. 409 421. Buchardt O. 205. Bucheck D. J. 202 502. Buchecker C. 173. Buchecker R. 40. Buchholz R. F. 107. Buchi G. 455. Buchs A. 17. Buck P. 275 333. Buck R. P. 7. Buckingham D. A. 79. Budding A. J. 298. Buchi G.,376 483 548. Buchi H. 490. Biihler R. E. 213. Biither H. 275. Biittner H. 172. Bugg C. E. 58 301. Buhl D. 491. Buick A. R. 31. Buist G.J. 83. Bull H. 74 150. Bull J. R. 37 421. Bullen G. J. 282. Bullock A. T. 33. Bullock G. A. 444. Bu' Lock J. D. 554. Bulten E. J. 298. Bunbury D. St. P. 307. Bunce R. J. 280. Buncel E. 79. Bunnenberg E. 41. Bunnett J. F. 99 181 338. Bunton C. A. 63. 68 80 81 83 88 100. Burbach-Westerhuis G. J. 530. Burczyk B. 405. Burdon J. 182 267. Burger U. 266 373. Burgess. E. M. 251. Burgess R. R. 521. Burgstahler A. W. 403. Burk L. A. 412. Burke J. J. 63. Burke P. L. 285. Burkoth T. L. 169. Burlachenko G. S. 295. Burley J. W. 274 276. Cameron A. F. 44 50. Burlingame A. L. 541. Cameron A..M. 79. Burlinson N. E. 65 135 Camilletti G. 62. 136. Campbell A. D. 73. Burlitch J. M. 279.Campbell G. A. 335 376. Burnell R. H. 55 480. Campbell H. F. 478. Burnett A. R. 542. Campbell I. M. 524 532 Burny A. 515. 555. Burrows H. D. 69. Campbell J. G. 182. Bursey M. M. 7 9 11. Campbell J. R. 250. Burton C. S. 196. Campbell R. A. 173. Busch D. H. 465. Busch P. 378. Campbell R. O. 198. Busetti V. 50. Campbell R. V. M. 350. Bushweller C. H. 328 371. Campbell W. J. 328. Buss V. 106. Campioli D. 64. Bussey R. J. 188. Candlin J. P. 306. Butcher M. 338. Canfield N. D. 30. Buter J. 162. Cannon J. G. 260. Butin K. 281. Cano F. H. 46. But’ko Y.D. 281. Canonica L. 552. Butler A. R. 94 95. Cantor C. R. 510. Butler I. S. 309. Cantor H. 507. Butler J. R. 356 392. Capecchi M. R. 517. Butler R. 94 267. Capellos C. 2 1 1. Butsugan Y.,432.Butterfield R. O. 242. Caple R. 146. Buzzolini M. G. 158 316 Capon B. 74. 400. Caprioli R. M. 7 10 11. Bychkov V. T. 279. Carbonaro A. 307 319 Bycroft B. W. 164. 320. Byram S. K. 286. Carboni G. 128. Cardenas C. G. 159. Cardillo M. J. 373. Cardinale G. J. 562. Caccamese S. 328. Cardinali G. 100. Cadet J. 505. Cargill R. L. 386. Cadogan J. I. G. 34 84 Cargiol J. D. 64. 100 175 181 341 461 Carlassare F. 503. 462. Carles J. 8. Cagen L. M. 558. Carlson G. R. 163. Cahn R. S. 36. Carlson J. A. 455. Cain E. N. 138 159 329. Carlsson L. D. 97. Cainelli G. 25 1 277. Caropreso F. E. 301. Cairns J. 504. Carpenter A. K. 233. Calabrese J. C. 53. Carpino L. A. 170 250 Calas R. 255 289 290. 434. CiildAraru H.35. Carrick W. L. 250. Calder A. 21 177. Carrington A. 177. Calder I. 352. Carrona T. 178. Calderon M. 533. Carson M. S. 405. Caldow G. L. 315. Carson M. W. 140. Caldwell R. A. 195. Carter J. V. 102. Calvin G. 310. Carter R. E. 328. Calvin M. 491 531. Cartlidge D. M. 403. Camaggi C. M. 181. Carty T. 77 18 1. Cambie R. C. 415. Caruthers M. H. 490. Camerman A.,49 58 202 Casey C. P. 307 310. 501. Casey J. P. 305. Camerman N. 58 202 Casper A. 12. 501. Caspi E. 541. Author Index Cassady J. M. 543. Cassar L. 158 315 323 400. Casson D. 31. Castagnoli N. 179. Castellano E. 417. Castillo F. 568. Castillo M. 546. Castle R. B. 280. Cattania M. G. 100 126. Catterall E. 287. Caubere P. 263. Caughey W. S.442. Caughlan C. N. 52 56 407. Cauquis G. 220 227 228 229 240. Cava M. P. 346 472. Cavalca L. 46. Ceccon A. 143. Cellura R. P. 162 174 463. Cercek B. 208. Cerefice S. A. 400. Cernjr M. 242 452. Cerutti P. A. 505. Ceveda M. L. 128. Cevestri R. C. 142. Chadha J. S. 530. Chaffin T. L. 428. Chakraborty D. P. 479. Chalfont G. R. 34 341. Chalk A. J. 294 312. Challis B. C. 91. Chalmers A. M. 221 374. Chalvet O. 90 204. Chamberlain T. R. 198. Chambers D. B. 276. Chambers J. Q. 30 227. Chambers K. W. 208. Chambers R. L. 300. Chambers R. O.,247. Chambers R. W. 510. Chambers V. M. A. 280. Chan E. 73. Chan S. I. 506. Chan T. H. 258 295. Chan W. R. 423. Chance R. E. 501. Chandra G.,298.Chandraseken R. 59. Chang E. 258 295. Chang R. 18. Chang S. 365. Chang S. Y.,19 20. Chapelle A. 55 480. Chapman N. B. 73. Chapman 0. L. 155. Chappell G. A. 129. Charalampous F. C.,573. Charleston B. S. 147. Charman H. B. 312. Author Index Charney E. 42. Chassin C. 243. Chastrette M. 263 278. Chater R. B. 339. Chatrousse A. P. 100. Chatt J. 308 324. Chatterjee N. K. 518. Chattopadhyay J. K. 369. Chaudri B. A. 39. Chaudron T. 279. Chauviere G. 302. Chauvin M. 278. Chauvin Y. 3 17. Chen C. 92. Chen C. M. 494. Chen D. 539. Chen 1. W. 573. Chen J. P. 409. Chen Chang J. H. 93. Cheng Y.-M. 139. Chernoff H. C. 453. Chernokal’skii B. D. 305. Chernyshev E.A. 293. Cherry A. J. 313. Chessin M. 212. Cheung A. C. 491. Cheung H. C. 41 1. Cheung H. T. 420. Cheung J. J. 381. Chheda G. B. 494. Chiang J. F. 368 372. Chien J. C. W. 180. Chihora H. 116. Chirpich T. C. 562. Chiu M. F. 19 24. Chiurdoglu G. 136. Chivers T. 272. Chlebicki J. 405. Cho M. H. 67. Chong J. 113. Chong J. A. 379. Chong Y. K. 16. Chooi S. Y. 73. Chothia C. 60. Chow H. S. 350. Chow Y. L. 171. Chowdhury B. K. 472. Christe K. O. 30. Christen J. D. 111. Christie P. H. 530. Christie W. W. 523. Christmann K. F. 258. Christy P. F. 90. Chu J. Y.-C. 163. Chu S.-C.,46. Chu W. 232. Chua A. S. Y.,437. Chugh 0. P. 410. Chung A. 518. Church R. B. 506. Churchill M. R. 307.Chutny B. 210. Ciabattoni J. 101 173. Cieresko L. S. 413. Ciganek E. 174 304 305 370. Cima F. D. 100. Cinquini M. 42. Cioffari A. 277. Ciorhescu E. 36 1. Ciuffarin E. 89 13 1. Clandy J. C. 157. Clapp L. B. 437. Clapp R. C. 56. Clardy J. C. 50 55 475. Claridge R. F. C. 3 1. Clark A. 316 570. Clark C. R. 74. Clark D. T. 106. Clark G. R. 57 473. Clark G. W. 182 341. Clark K. W. 478. Clark M. 247. Clark M. J. 562. Clark N. H. 282. Clark P. W. 31 1. Clark R. T. 86 302 303. Clarke B. 318. Clarke D. G. 479. Clarke T. G. 249. Claxton T. A. 18 20. Clayton J. D. 495. Clayton R. B. 541. Cleaver J. E. 505. Clegg A. S. 425. Clement W. H. 314. Clemente D. A. 301. Clementi S.,94,97 340.Clements J. A. 529. Cleveland J. P. 89. Clews C. J. B. 46. Clezy P. S. 441. Clifford P. R. 116 132. Clinton N. A. 110 125. Clive D. L. J. 260. Cloarec L. 429. Closs G. L. 23 172 179. Closse A. 40. Closson W. D. 112. Coates G. E. 272 276 310. Coates R. M. 109 405 407 409 410. Coburn R. A. 56. Cochoy R. E. 296. Cochrane W. P. 437. Cocivera M. 178. Cocker W. 405. Cockerill A. F. 63 65 135 366. Coe P. F. 493. Coe P. L. 267. Coffen D. L. 30. Coffey R. S. 31 1 319. Coggon P. 47 55 56 62 302. Cohen B. I. 493. Cohen G. 471. Cohen G. H. 57. Cohen L. A. 69 243 558. Cohn M. 521. Cohen S. C. 272. Cohen S. G. 196. Cojazzi G. 50. Colby C. 508. Cole F. E. 59. Cole S.J. 57. Coleman J. P. 235 236. Coles L. 531. Colin G. 259. Coll J. C. 463. Collier M. R. 273 310. Collington E. W. 261 459. Collins C. J. 117. Collins D. M. 442. Collins M. 47 1. Collinson E. 208. Colomber E. 376. Colonna S. 42. Colowick S. P. 566. Comer F. 547. Commeyras A. 116. Commoner B. 490. Conacher H. B. S.,525. Concannon P. W. 173. Conia J. M. 253 257 336 377 379 384. Conkling J. A. 118. Conner M. K. 461. Connolly J. D. 418 422. Connon N. W. 90. Connor H. D. 33. Connor J. A. 308. Connors K. A. 72. Connors M. J. 569. Connors P. G. 509. Considine W. J. 278. Cope A. C. 190. Coppens P. 53. Cook A. F. 495. Cook C. 316. Cook I. F. 414. Cook J. 341. Cook M.A.. 274. 280. 295. Cook P. M. 179. Cook R. D. 85 302. Cook T. H. 277. Cooke M. P. 265 324. Cooke R. G. 455. Cooks R. G. 11 16. Coombes R. G. 90. Coombs R. 428. Cooper A. 62. Cooper B. J. 242. Cooper G. W. 263. Cooper J. 90. Cooper J. T. 30. Cooper R. D. G. 439. Corbett G. E. 96. Corbin J. L. 56. Cordell G. A. 483 543. Cordes E. H. 74 150. Cordone L. 504. Corey E. J. 164 246 253 257 258 264 268 303 304 310 374 410 411 414 525 526 527 528. Corfield J. R. 85 87 301 302. Corina D. L. 573. Cornforth J. W. 250 435 536 561. Cornforth R. H. 243. Corolleur C. 12. Corolleur S. 12. Corradini P. 44. Corrie T. E. T. 41 1. Corriu R. 42 145. Corriu R. J. P. 292. Corson F.P. 385. Corvelisse J. 198. Cory S. 514. Coscia C. J. 406. Cosgrove R. E. 245 276. Costilow R. N. 562. Cotterrell G. P. 421. Cotton F. A. 286. Couchman G. L. 368. Counsell R. E. 427 428 430. Courbis P. 230. Court J. 182. Courtot P. 167. Courtot-Coupez J. 240. Cowan D. O. 196. Cowan J. C. 528. Cowell G. W. 172. Cowley D. J. 26 34. Cox B. G. 64 138. Cox G. W. 53. Cox J. M. 57 426. Coxon J. M. 406. coy u. 535. Coyle J. D. 200. Craddock J. H. 322. Cragg G. M. L. 428. Cragg R. H. 268. Craig J. C. 40 77 179. Craig M. 521. Craig M. E. 507. Cram D. J. 139,350 383. Cramer F. 495 498 510. Crampton M. R. 98. Crandall J. K. 406. Craven B. M. 53 61. Crawford J. W. 386. Creary X.69. Creasy W. S. 303. Creese M. W. 144. Creger P. L. 261. Cremer H.-D. 354. Cremer S. E. 86. Cretney J. R. 331. Cretney W. J. 483. Crick F. H. C. 489,490. Criegee R. 355 358. Crist D. R. 162. Cristol S. J. 362. Croatto U. 301. Crociani B. 308 324. Crofts P. C. 300. Crombie L. 350,479 556. Crosby J. 141. Cross B. E. 414 540. Cross R. J. 280 294. Crossland R. K. 266. Crothers D. M. 506. Crout D. H. G. 547. Crow W. D. 457. Crowell T. I. 130. Crowther G. P. 274. Crumrine A. E. 203. Csizmadia I. G. 65 136. Cuddy B. D. 114. Cullen W. R. 297. Culvenor C. C. J. 467 468. Cundall R. B. 196 208. Cuppen T. J. H. M. 199. Cuppers,H. G. A. M. 310. Curdy C. S. 321. Currie J. O.439. Currie M. 52. Curtis R. F. 552. Cusack N. J. 452. Cusatis C. 61. Cuvelier C. 370. Cvetanovic R. J. 21 1. Czapski G. 28 208. Czuba L. J. 259. Dabovic M. 428. Dafforn G. A. 113. Dahl T. 51. Dahlberg J. E. 490. Dabm D. 475. Dahn H. 80 115. Dai S. H. 156 160. Dainton F. S. 208. Dale J. A. 268 371. Dallas G. 345 433. Dall’ Asta G. 319 320. Daloze D. 136. Author Index Dalrymple D. L. 303. Dalton C. K. 147. Dalton D. R. 21 147 149. Dalton J. C. 195 200. Daly J. J. 52 301. Daly J. W. 40 205 436 486. Daly W. H. 144 251. Damerau W. 28. Damodaran N. P. 495. Danen W. C. 27 33. Danforth R. H. 250 288. D’Angelo R. 310. Daniel D. S. 408. Danielsson H. 528. Dannenberg H.249 427. Dannley R. L. 96. Danzel A. 15I. Danzer W. 134 168. Darby A. C. 94 267. Darensbourg D. J. 307. Darensbourg M. V. 307. Darling S. D. 245 276. Darnall K. R. 435. Darragh K. V. 172 280 375. Das B. C. 474. Das B. P. 174. Das C. K. 149. Das M. R. 33 515 Das N. C. 178. Das R. 479. Daste Ph. 418. Daub J. 105. Dauben W. G. 155 158 201 244 316 383 400. Daudel R. 90 204. Dave H. R. 440. Davidson B. E. 567. Davidson E. R. 19 20 Davidson R. S. 28. Davies A. G. 26 27 284 305. Davies A. P. 530. Davies D. B. 496. Davies D. R. 57. Davies J. V. 216. Davies N. M. 547. Davies R. E. 43 44. Davis C. E. 79. Davis D. D. 300. Davis F. A. 337. Davis J. P. 496. Davis K.P. 312. Davis R. E. 79. Davis V. E. 47 1. Davis W. R. 275. Davison A. 165. Dawson D. J. 422. Dawson M. I. 263,422. Day M. C. 286. Day R. S. 502. A uthor Index Deacon G. B. 272 282 289. Deady L. W. 73. de Amezua M. G. 447. Dearden G. R. 441. De’ath N. J. 85 302. De Backer M. G. 212 245 465. Deberitz J. 302. de Bernardis J. 139. De Boer A. 383. de Boer Th. J. 11 12 34 201 205. de Camp W. H. 50. Decazes J. 157. Deckers F. H. M. 445. De Clercq E. 508. de Crombrugghe B. 522. Dedier J. 289. Degani I. 21. Degener E. 448. Deghenghi R. 424. de Haan J. W. 165 167 397 398. de Haas G. H. 530. Dehmlow E. V. 14 388. Deines W. H. 135 168. Dekker E. E. 562. Dekker J.359. de la Fuente G. 135 338. de la Mare P. B. D. 93 149 331. Delany F. B. 17. Delaplane R. G. 53. Delazarche A. 249. Del Cima F. 100. Delfino A. B. 17. Della Casa de Mareano D. P. 417. Delpuech J. J. 65. de Lucie P. 504. de Marcano D. P. D. C. 38. de Mayo P. 14. De Member J. R. 104,116. Demeo D. A. 367. Demerseman P. 259. Demerson C. 486. Demole E. 412. den Hollander J. A. 327. Denise B. 277. Denisov E. T. 177. Denney D. B.. 275. Dennis N. 408. Dennis W. E. 294. Deno N. C. 103 248 262. Dent S. P. 312. De Puy C. H. 383. De Renzi A. 324. Dergan 0.N. 245. de Rossi R. H. 341. de Rostolan J. 428. Doepner H. 510. Dertinger H. 29. Doering W. von E. 391. Derys M. 423. Dotz K.H. 308 375. de Santis P. 62. Dohrmann J. K. 20. Deschamps J. 493. Dolak L. A. 246. Deshpande R. 96 196. Dolan E. 282. Desiderio D. M. 497. Dolbier W. R. jun. 156 Deslongchamps P. 450. 160 392. Dessau R. M. 29 191 DolejS L. 472 494. 192. Dolfini J. E. 422. Destro R. 44. Dolgoplosk B. A. 317. De Tar D. F. 181. Dolhun J. J. 13 14 497. Deubzer B. 305. Dolphin D. 442. Deutsch J. 13. DoMinh T. 157 161. Deutschman A. J. 526. Donohue J. 489. Devaprabhakara D. 379. Donohue J. A. 64. Devgan 0.N. 276. Donzel A. 75. Devon T. J. 337. Doolittle W. F. 51 1. Dewar M. J. S. 106 109 Doorakian G. A. 169. 110 153 154 164 174 Doppler-Bernardi F. 493. 191 286 327 365 461 Dorfman L. M. 208 209 492. 212. Dewar P. S. 188 357. Doria G. 262.Dewey K. 517. Dorman D. E. 366 497. Dewick P. M. 556. Dornauer H. 304. Dheer S. K. 498 501. Dornhege E. 39. Dias J. R. 244. Dorsey E. D. 157. Diaz A. 119. Doskotch R. W. 423. Dickason W. C. 243 283 Doty P. 512. 384. DOU H. J.-M. 182. Dickerman S. C. 21. Dougherty R. C. 8. Dickinson C. 61. Douglas J. R. 328. Dickinson L. C. 24. Doumaux A. R. 247. Dieffenbacher A. 388. Doupeux H. 238. Diekman J. 9 12. Dowd P. 155 156 199 Diem F. 292. 365. Dietl H. 318. Dowden B. F. 165. Dietrich B. 465. Down J. G. 455. Dietrich V. H. 45. Downing A. P. 328. Dietz R. 224 239. Doyle M. P. 112 114 Dijkink J. 450. 374 386. Dik J. K. 198. Doyle T. W. 355. Dilling W. L. 153. Dozsai L. 96. Dimroth P. 553. Drabkina A. A. 407 523. Diner U.E. 149 254. Dradi E. 262. Dirheimer G. 508. Drake J. E. 273. Ditmar W. 380. Draper P. M. 11. Dittmer J. C. 523. Dreiding A. S. 41 388. Diversi P. 367. Dreux J. 357. Dixon J. 430. Driguez H. 255. Dixon J. E. 138. Driscoll G. A. 568. Dixon W. T. 90. Driver G. E. 86 303. Djerassi C. 8,9 11 12 15 Drozd J. C. 247. 17 37 39 41 55 422 Drum D. E. 570. 424 43 1 480 482. Dua S. S. 300. Doak G. O. 271. Dubac J. 295. Dobbs A. J. 20. Dub& S. 450. Dobereiner V. 574. Dube S. K. 508. Dobis I. 91. Dubois E. 451. Dockus C. F. 295. Dubois J. E. 97 148 219 Doddrell D. 379. 231. Dodgson K. S. 216. Dubsky G. J. 278. Duckworth. J. A. 5 1. Ducois J. 65. Ducom J. 277. Dudek G.O. 497. Dudock B. S. 509. Dueber T.G. 126. Duebo J. M. 79. Dueltgen R. R. 404. Durr H. 173. Duesberg P. H. 508. Duwel H. 101 353. Dufay P. 493. Dufek E. J. 528. Duff J. M. 274. Duffaut N. 289,290. Duffin D. 168 254 377 379. Duke A. J. 384 388. Duke J. R. C.,388. Duke R. P. 330. Dull D. L. 268. Duncan W. P. 267. Dunikoski L. K. 87. Dunn B. M. 74 132. Dunn G. E. 64. Dunn J. J. 521 522. Dunne K. 320. Dunogues J. 289 290. DuPree L. E. 442. du Preez N. P. 359. Durst H. D. 243. Dust L. A. 192. Dutton H. J. 533. Dutton J. H. 523. Dvolaitzky M. 243. Dyatkin B. L. 137 281. Dye J. L. 212 245 465. Dyer J. K. 562. Dqgos D. K. 124. Dyke T. 365. Dyson W. H. 494. Dzhomidava Y.A. 28 1. Eaborn C.,20 96 97 274 280 294 295 300 312 330.Eachus S. W. 340 463. Eadon G. 9 11. Earl G. W. 114 266. Eastlick D. T. 84 100. Eastman. R. H. 179. Eastmond R. 97. Easton N. R. 327 433. Eastwood F. W. 262. Eaton J. T. 327 433. Eaton P. E. 158 315,400. Ebel J. P. 512. Eberhardt G. C. 317. Eberson L. 225 226. Ebert M. 213 214 215 216 505. Eckert C. A. 158. Eckhard I. F. 182 341 342. Eckhardt G. 37. Eckstein F. 495 496 498 508. Edens R. 190. Edgar J. A. 468 Edge D. J.,29 139 188. Edmondson R. C. 276 300. Edward J. T. 324. Edwards J. O. 84. Effenberger F. 266. Efraty A. 402. Egan W. 302. Eggins B. R. 227. Eguchi G. 304 Eguchi S. 460. Ehmann W. J. 245 318 333. Ehntholt D. J. 307 349.Ehresmann C.,5 12. Eian G. A. 64. Eibl H. 530 531. Eigen M. 507. Eilers N. C. 13. Eisch J. J. 278 287. Eisele B. 570. Eisenberg F. 573. Eisenbraun E. J. 468. Ekong D. E. U. 421. Ekstom B. 439. Elad D. 503. El-Anani A. A. 95 363. el Dusouqui 0. M. H. 92. El Ghariani. M. 98. Elian M. 305 361. Eliel E. L. 13 242 384 456. Elix J. A. 462. El-Kady. I. 425. Ellestad G. A. 412. Elliott W. H.,574. Ellis A. W. 445. Ellis J. 63. Ellis R. M. E. 501. Ellison R. A. 414. Elmes P. S. 305. Elmore N. F. 50. EINadi A. H. 80. Elovson J. 532. El-Refai A.-M.,425. Elsam L. F. 265. Elsworthy G. C. 549. Elwood T. A. 9 11. Emel'yanov I. S. 152. Emergy A. 323. Emerson G. F. 307. Emerson M.T. 56 407. Emmer M. 522. Emmerson P. T. 214. Author Index Emmert D. E. 443. Emsley J. W. 21 177. Enderer K. 393. Endo K. 355. Endres R. 31 1. Engberts J. B. F. N. 34. Engel J. 506. Engel J. F. 302. Engel P. S. 188. Enggist P. 412. Englard S..41. Enslin P. R. 37. Entenmann G.,458. Epling G. A. 203. Epstein J. H. 505. Erdman A. A. 281. Erdman T. R. 357. Erdohelyi A. 96. Erdtman H. 37. Erickson J. L. 49. Erickson K. C.,260 370. Erickson R. E. 237 247. Erickson W. F. 179. Erman W. F. 412. Eron L. 490. Errera M. 504. Ertel I. 232. Eschenmoser A. 440. Escher S.,406 536. Eschinasi E. H. 405 408 Espaiia de Aguirre A. G. 467. Essenberg M. K. 560. Estham J. F. 275. Estienne M.230. Etemadi A. H. 524. Etlis V. S..434. Eugster C. H. 40. Euranto E. K. 279. Evans A. G. 33. Evans. B. W. 88. Evans D. A. 17. Evans D. F. 310. Evans H. 97. Evans J. C.,33. Evans N. 570. Evans R. 539. Evans R. H. jun. 412 552. Everett A. J. 473. Everett G. A. 498. Everse J. 568. Ewing D. F. 90. Exner O. 65. Eyring H. 37 496. Ezimora G. C. 388. Ezzell B. R. 301 303. Faber D. 493. Fahey D. R. 313. Fahey R. C. 145. Fahnestock S. 517 Author Index Fahr E. 156 501. Faita G. 223. Fajer J. 442. Falcetta J. 39. Fales H. M. 14 467 545. Falk H. 39. Falle H. R. 21. Falmor W. 15. Fantechi R. 19. Farber S. J. 81. Farid S. 159 202. Farina M. 40. FarkaS J. 494.Farlow D. W. 64. Farmer M. L. 319. Farnham W. B. 302. Farnsworth N. R. 62. Farnum D. G. 163. Farr F.. 3 1 340. Farrant G. C. 163 354 391. Farrier D. S. 55 477 478. Farve A. 510. Fasman G. D. 40. Faubl H. 379. Faulkner D. J. 252 382 528. Faure-Raynaud M. 418. Fauvarque J. F. 277. Faux A. 16. Fava A. 89 13 1. Favilla R. 569. Favre. A. 512. Fawcett J. K. 45 286. Fayez M. B. E. 471 545. Fazakerley G. V. 310. Fazakerley H. 267 429. Feakins P. G. 430. Fedeli W. 49. Fedor L. R. 142. Fedorov L. A. 272. Feeley T. M. 42. Feher F. 45. Fehler S. W. G. 531. Fehr T. 14. Feigenbaum E. A. 17. Feingold D. S. 574. Feit B. A. 148. Fel’dblyum V. S. 317. Felder P. W. 282. Feldmann R.101 163 353 354 391. Felix A. M. 14. Felkin H. 167 263. Fellner P. 5 12. Felsenfeld G. 493 506. Felton R. H. 442. Felton S. M. 75 151. Fendler E. J. 68 87 99 100 177 339. Fendler J. H. 68 87 99 100 177 339. Fenical W. 155. Fenje P. 490. Fenn D. J. 88. Fennessey J. P. 54 307. Fenoglio R. A. 122. Fenster A. E. 309. Fentiman A. F. 96 116 119. Fenton D. F. 132. Fentrill G. R. 130. Feoktistov L. G. 239. Ferguson G. 44 54 62 321 424 487. Ferguson L. N. 382. Ferles M. 449. Fernando Q. 50. Ferrari A. 279. Ferrari M. 418. Ferrer-Correia A. J. 7. Ferrier R. J. 452. Ferris J. P. 491. Fersht A. R. 77. Fessenden R. W. 19 28 21 1. Festal D. 449. Fetizon M. 38 426. Feunteun J.51 1. Feutrill G. I. 268. Fickes G. N. 177. Fiebig A. 140. Field A. K. 507. Field F. H. 14. Fielden E. M. 213 215 217 218. Fields E. K. 182. Fields R. 281 301. Fife T. H. 72 73 74. Figeys H. P. 355. Filby W. G. 14. Filipescu N. 361. Filippinni G. 44. Filler R. 30 140 267. Finch A. 272 282. Finckh R. E. 455. Findlay D. 496. Findlay J. A. 528. Findlay J. W. A. 334. Finkelstein M. 192 225 231. Finocchiaro P. 328. Fiorti J. A,,432. Firestone R. A. 160. Fisanick G. J. 372. Fisch M. 191 197 373. Fisch M. E. 477. Fisch M. H. 174 386. Fischer A. 323 331. Fischer C. M. 237. Fischer E. O. 305 307 308 324 375. Fischer H. 20 23 27 341. Fischer N. 41. Fischer R.D. 307 308. Fish R. W. 95. Fishbein R. 262. Fisher F. 122. Fisher G. J. 501. Fishwick M. 287. Fitzgerald R. 385 Flanagan P. W. K. 65 136. Flateau K. 281. Fleischer E. B. 440. Fleischer R. 364. Fleischman P. 490. Fleischmann M. 223,240. Fleming I. 171 398 449. Fletcher H. G. 573. Fletcher J. W. 212. Fletcher R. 125. Fletcher V. R. 384,428. Flippen J. L. 53. Fliszar S. 8. Flood J. 93. Flood M. E. 555. Flood W. W. 221 374. Florencio F. 46. Florent’ev V. L. 449. Floss H. G. 543. Flowerday P. 342. Floyd M. B. 526 527. Flygare W. H. 372. Flynn C. R. 121 448. Flynn J. J. 320 402. Foa M. 232. Foglia T. A, 529. Fojtik A. 208 209 210. Foley A. J. 100. Foley K. M. 244. Folkers E.A. 428. Follmann H. 493 561. Follweiler D. M. 105. Folsom T. K. 260 370. Foltz R. L. 8. Fondy T. P. 568. Fong C. W. 272,295,299. Font J. 348. Foote C. S. 120 155 204 440. Forbes W. F. 30. Ford G. C. 567. Ford P. W. 154. Ford W. T. 161 343. Foreman M. I. 314. Forget B. G. 512. Forkey D. M. 50,447. Forno A. E. J. 24. Forrester A. R. 21 177 188 357. ForSek J. 41 428. Forsellini E. 324. Forshult S. 25. Forster D.. 349. Foster A. M. 386. Foster D. M. 79. Foster M. A. 564. Foster R. 97. Fournier J. 373. Fowler J. S. 250 288. Fox D. B. 324. Fox S. W. 491. Fox W. B. 20. Fox W. M. 29. Foy P. 426. Fraenkel G. K. 31. Frainier L. 136. Francis M. J. O. 406 537.Franck B. 468. Franck R. W. 157. Francke B. 514. Franck-Neumann M. 173. Frangopol P. T. 26. Franich R. A. 415. Franier L. 65. Frank E. 307. Frank J. A. K. 309. Frank R. W. 341. Frankel E. N. 242 313 523. Frankfater A. 566. Franzen V. 190. Fraser R. R. 440. Frasnelli H. 274. Frater Gy 167 173 335. Fratini A. V. 48. Frecke A. 243. Frederick R. 335. Fredericksen J. D. 237. Frediani P. 322. Freed J. H. 33. Freedman H. H. 102 169 328. Freedman L. D. 27 I 303. Freeman F. 150. Freeman G. R. 21 I. Freeman P. K. 121. Freist W. 498. Freon P.,279. Fresco J. R. 57 509. Freter K. 45 1. Frew D. 51,449. Frey H. M. 157 169 395 397. Frey P. A. 559 564. Fric I. 40. Fridovich I.566. Friebolin H. 349. Fried I. 240. Friedinger R. M. 410. Friedmann H. C. 558,562. Friedrich E. C. 108 168. Friedrich J. P. 528. Fringuelli F. 96. Fritchie C. N. jun. 59. Fritsch J. M. 30 228. Fritschi G. 375. Author Index Fritz G. 292. Gall M. 259 328. Fritz H. P. 305. Gallagher M. J. 86 303. Frosst A. I. 142. Galle J. E. 304. Frost K. A. 385. Gallerani R. 515. Fry A. J. 238. Galli R. 178. Fry E. M. 480. Gallo R. C. 516. Fry J. L. 104 106 114. Gamble A. A. 8. Fry L. 110 111. Gamo M. 529. Frye C. L. 149 293. Gandemer A. 144. Frye R. L. 220. Gandhi S. S. 472. Fueno T. 147 158 226 Gandolfi C. 262. 390. Ganguli G. 478. Fuganti C. 548. Gansow 0. A. 305. Fuhrhop J.-H. 441. Ganter C. 454. Fujiawa Y.325. Garapin A. 507. Fujii S. 491. Garbutt G. B. 20. Fujimori K. 184. Garcia-Blanca S. 46. Fujimoto T. 423. Gardini C. P. 178. Fujinaga K. 515. Gardner P. J. 272 282. Fujioka S. 16. Gardner R. J. 244. Fujisawa T. 336. Garen A. 517. Fujise Y. 162. Garin D. L. 394. Fujishima I. 331. Garland R. P. 406. Fujita S. 406. Garnett G. L. 312. Fujita T. 266. Garratt P. J. 162 303 Fujita Y. 20 406. 349 354 355 359 445 Fujiwara Y. 333. 464. Fuks R. 449 451. Gasche J. 524. Fukumoto K. 472. Gascosian R. B. 140. Fukunaga K. 170. GaSiC M. 428. Fukuoka M. 421. Gaskell A. J. 479. Fukuoka S. 324. Gaspar P. P. 173. Fukuyama K. 505. Gasparri G. F. 46. Fukuyama M. 65 136. Gassman P. G. 96 115 Fulmor W. 459 494. 116 119 124 274 335 Funk F.493. 376. Funke E. 407. Gast E. 283. Funt B. L. 222. Gast L. E. 528. Furukawa H. 474. Gatenbeck S. 551. Furukawa J. 158 266 Gates M. 471. 320 390,401. Gatfield I. L. 416. Furukawa N. 336. Gaudiano G. 258. Furukawa Y. 491 529. Gaul J. M. 244 290. Furusaki A. 62. Gault F. G. 12. Gault I. R. 328. Gawad D. H. 479. Gaasbeek C. J. 103 105. Gawne G. 492. Gabbay E. 502. Gay D. C. 86. Gabriel O. 574. Gaylor J. L. 542. Gabrielsen R. S. 180. Gazit A . 349. Gabrielson B. 109. Gebrian J. H. 463. Gaffield W. 39. Gee D. R. 35. Gagen J. E. 96. Gefter M. L. 51 1. Gaibel Z. L. F. 383. Geiger W. 448. Gaidis J. M. 298. Geiger W. E. jun. 30. Gajewski J. J. 123 391 Geise H. J. 368. 393. Geissman T. A. 407,413. Gajewski R. P. 123.Gelbcke M. 355. Galantay E. 347. Gel’fond A. S. 305. Galanty E. 428. Gelius R. 299. Galbraith M. N. 16 418. Gelpi E. 531. Gall B. L. 209. Geluk H. W. 34 114. Author Index Gelus M. 182. Gemmell K. W. 57. Genies. M. 228 229. Gender W. J. 526 527. Geoghegan P. J. 255. George D. J. 565. George T. A. 336. George T. J. 456. Gerdil R. 238 239. Gerig J. T. 369. Gerlock J. L. 22. Germain G. 59. Gerner T. H. 278. Gero. S. D. 144. Gerson F. 32. Geske D. H. 25. Gesser H. D. 20. Gesteland R. F. 490. Gesting P. 32. Getoff N. 210. Geuss R. 278. Ghambeer R. K. 561. Ghera E. 345. Ghisalberti E. L. 417,418. Ghosez L. 435. Giacobbe T. J. 412. Gianangeli M. 1 11. Gianni M. A. 185. Giannini U.310. Gibson J. W. 58 59 501. Gibson M. S. 473. Gick W. 300. Gierin A. 45. Gierke T. D. 372. Giersch W. 41 1. Giese R. W. 33 245. Giezendanner H. 8. Gil-Av E. 13. Gilbert A. 96 196 197. Gilbert B. C. 20 24 25. Gilbert J. C. 356 392. Gilbert J. M. 518. Gilbert J. R. 8 65 135. Gilbert W. 521. Gilde H. G. 236. Gill E. W. 192. Gill G. B. 177 191 315 387. Gillan T. 187. Gillard R. D. 314. Gilles J.-M. 354 372. Gillessen D. 14. Gilman H. 276 291 300. Gilmore J. R. 192. Gindici T. A. 74. Ginsburg D. 366 398. Girgenti S. J. 428. Gitlitz M. H. 278. Guidici T. A, 454. Givot 1. L. 565. Gladych J. M. Z. 263. Gladysheva F. N. 434. Glaser L. 573 574. Gleason J. G. 262 268.Gleicher G. I. 121. Gleiter R. 172 275 333 367. Gletsos C. 483. Glockling F. 276 287. GIockner P. 309. Glotter E. 432. Glushkov R. G. 449. Godden E. H. 33. Godet J. 244. Godtfredsen W. O. 14. Gotz M. 485. Goh L. Y. 279. Goh S. H. 279. Gohlke R. S. 12. Goi M. 412. Gol A. 128. Golankiewicz K. 501. Gold A. 155 199. Goldberg I. B. 31. Goldberg S. I. 469. Goldman; D. S. 53 1. Goldstein G. 491. Goldstein M. J. 104 165 183. Gommper R. 153 157 Gonzalez A. G. 467. Gonzalez E. 252. Goodacre G. W. 52 301. Goodchild J. 498. Goode G. C. 7 Goodfellow D. 40. Goodman D. 518. Goodman H. M.,490,515. Goodman L. 495. Goodman M. 39. Goodwin D. G. 39. Goodwin S. L. 13. Gopalakrishna E.M. 62. Gordon E. M. 472. Gordon M. 360 367. Gore P. H. 96. Gormish J. F. 247. Gornowicz G. A. 295. Gosavi R. K. 173. Gosling K. 287. Gosnell J. L. 369. Gotkis J. K. 77. Gottarelli G. 36. Gottesman M. M. 561. Gotthardt H. 160. Gottlicher S. 50. Gough T. E. 25. Gougoutas J. Z. 55. Could R. R. 37. Gourley R. N. 234. Govindachari T. R. 470 472. Goyan J. E. 73. Goyert G. 344. Gracey D. E. F. 14,473. Grady G. L. 292. Graf F. 35. Graf G. 304. Graham K. 444. Gramaccioli C. M. 44. Gramain J. C. 191 373. Granik V. G. 449. Grant D. H. G. 90. Grant D. M. 497. Grasselli P. 251 277. Graves J. M. H. 570. Gray D. G. 222. Gray G. M. 531. Gray R. T. 12. Grayshan R. 429. Grayston M.W. 436. Gream G. E. 190 345. Greco A. 307 319 320. Green D. T. 250 435. Green E. E. 220. Green F. D. 168. Green M. 310 318 321 515. Green M. M. 13. Greene F. D. 187. Greener G. P. 235. Greenfield N. J. 40. Greenstock C. L. 214,217. Gregoriou G. A. 110. Gregory B. J. 78. Gregory M. J. 68. Greifenstein L. F. 369. Greig C. C. 95 363. Greiss G. 282. Grethe G. 41 472 477. Grey A. A. 496. Grey D. 112. Grey S. 404. Gribble G. W. 327 328 433. Grieger R. A. 158. Griesbaum K. 127 157 177. Griffen W. P. 317. Griffin C. E. 99 339. Griffin G. W. 161 375. Griffin R. G. 24. Griffin R. H. 113. Griffiths A. 48. Griffith D. L. 83. Griffiths J. 134. Grigg R. 159 399 441 442 443.Griller D. 26 284. Grimes R. N. 271. Grimme W. 309 353 354. Grimmett M. G. 446. Grimshaw J. 33 234 245. Grimsrud E. P. 130. Grisdale P. J. 282. Grisebach H. 555 574. Griselli F. 131. Grob C. A. 112. Groger D. 467 543. Groen M. B. 445. Gromb S. 370. Groner Y. 5 17. Grootveld H. H. 278. Gros F. 512. Gross B. E. 416. Gross H. J. 450. Gross J. M. 33. Gross M. L. 73 113. Gross R. A. jun. 15 431. Grossman N. 66 334. Grossweiner L. I. 216. Groth P. 45 49 51. Grove J. F. 551. Grovenstein E. 139. Groves J. T. 101 344. Grubbs R. 226 346. Grubbs R. H. 307. Gruber G. W. 355. Griitzmacher H. Fr. 12. Grunbein W. 210. Grundon M. F. 337,469. Grutzner J. B. 104 105. Grzonka J.96 196 197. Gschwend H. W. 468. Guarnaccia R. 406. Gubelt G. B. 79. Giinther H. 170 309 354. Guenzet J. 145. Guest I. G. 426. Guillerm G. 281. Guinand M. 531. Guindy N. M. 70. Gulick W. M. jun. 25. Gund T. M. 382. Gunn P. A. 374. Gunstone F. D. 525 528 533. Gunthard H. H. 35. Gupta K. 15 43 1. Gupta N. 490. Gupta N. K. 518. Gupta R. N. 545 546. Gupta S. K. 265 285. Gurbaxani S. 41 1. Curd R. C.,23. Gurfinkel E. 252. Gurgo C. 515. Gusarov A. V. 152. Gusev A. I. 306. Gustaffson B. 61. Gutch C. J. W. 26. Guthrie R.D. 136. Gutowski G. E. 437. Guttormson R. 413. Gutzwiller J. 470. Hug A.. 299. Haag E. 285. Haake M. 266 375. Haake P. 79,80,85,87 302. Haas D.J. 57. Haberland U. 354. Habermehl G.. 421. Hach V. 403. Hachen-Mehri M. 482. Hackler R. E. 179. Haddon R. C. 103. Hadfield J. R. 483. Hadinec I. 407. Hadley S. G. 27. Haemmerle B. 220 240. Hagele G. 300. Haenel M. 350. Haring J. 461. Harle E. 417. Haerlin R. 493. Hafner K. 364 461. Hagberg C. E. 90. Hager G. D. 368. Hagihara N. 319. Hahlbrock K. 555. Haiduc I. 271 Hair N. J. 50. Hairston T. J. 295. Hale R.L. 15 431. Halen B. S. 116. Halford J. O. 120. Hall E. S. 483. Hall F. M. 63. Hallett F. R. 505. Hall J. B. 408. Hall R. E. 11 I. Hall R. F. 323. Hall R. H. 337 494. Hall S. S. 383 453. Halle J. C. 100. Hallett B. P. 505. Halleux A. 260. Halpern J. 72 158 306 315 400.Halsall T. G. 38 56 409 417 421. Haltiwanger R. C. 417. Hamada K. 522. Hamanaka N. 417. Hamasaki T. 549. Hamberger H. 101 328. Hamer N. K.. 86 166. Hamersman J. W. 124. Hamill H. 382. Hamilton E. J. jun. 26. Hamilton L. D. 490. Hamilton S. B. 93. Hamilton W. C. 43 60. Hamkalo R. A. 5113 520. Hammack E. S. 32 1. Hammarstrom. S. 531. Hammett L. P. 63 68. Hammond G. S.. 26 199 203. Author Index Hammond H. A, 113. Hampson N. A. 249. Han C.-H. 337. Han J. 531. Hanack M. 126 128. Hanaoka M. 40. Hancock R. A. 90. Hand R. 227. Handloser L. 123. Hankinson B. 343. Hanna I. 38. Hanner J. A. 321. Hansen G. R. 234. Hansen H. J.. 166 204 335. Hansen J. F. 233 463.Hansen L. K. 449. Hanson E. M. 280 290 294. Hanson G. C. 131. Hanson J. R. 245 413 427 538 539. Hanson K. R. 565 Hanson P. 24. Hanstein W. 107. Hanzlik R. P. 541. Harada F. 508. Harada H. 487. Harada N. 40. Harding K. 525. Hardman K. D. 496. Harger M. J. P. 301 341. Harget A. J. 492. Hargreaves M. K. 42,440. Harita K. 427. Harkiss K. J. 487. Harman B. N. B. 93. Harmer A. F. 345. Harms M. D. 445. Harper J. J. 114. Harper R. W. 424. Harpp D. N. 246 262 268. Harrell R. L. 278. Harrington K. J. 262. Harris D. L. 101 105 164 329 393. Harris J. C. 129. Harris J. I. 567 568. Harris J. M. 106 109 111. Harris M. R.. 498. Harris R.L. 456 Harris 'T. M. 553. Harrison A.G. 9. Harrison D. A. 178. Harrison E. A, 345. Harrison. H. R. 56. Harrison I. T. 254 375. Harrison J. M. 388. Harrison M. J. 125. Harrison P. G. 273. Author Index 59 1 Harrison W. B. 23. Hart E. J. 207 209. Hart H. 166 331. Hart P. A. 496. Hartke K. 347. Hartman K. A. 512 Hartman M. E. 256. Hartshorn M. P. 331,406 426. Hartsuck J. A. 57. Hartung H. 304. Hartwell G. E. 31 1 31 3. Hartzler H. D. 448. Harvey R. G. 244 360 361 367. Harvie I. 313. Hasan S. K. 250. Hasegawa H. 29. Haselbach E. 102 154 174 364. Hashimoto H. 320. Hashimoto I. 96. Hashimoto M. 494. Hashimoto S. 508. Hashimoto T. 533. Haslinger E. 468. Hassall C. H. 360 552. Hassan M. 92. Hassel O.51. Hassner A. 149 304 384 428 439. Haszeldine R. N. 182 281 301 317 341. Hatano H. 29. Hatano K. 469. Hathaway C. 80. Haufe J. 220. Haupt F. C. 177. Hausch S. 83. Hauser C. R. 139 274. Hauser F. M. 475. Hautala R. R. 199. Havinga E. 100 198 424. Havir E. A. 565. Hawkins E. G. E. 186. Hawks R. L. 477 478. Hawley M. D. 33 233. Hawryluk I. 493. Hay R. W. 67 7'4. Hayakawa K. 205 348. Hayama Y. 406. Hayamizu K. 533. Hayase Y. 416 444. Hayashi A. 530. Hayishi N. 407. Hayashi S. 403 407. Hayashi T. 417. Hayatsu H. 493 498. Hayes R. G. 32. Haynes P. 321 323. Hayon E. 215. Haywood-Farmer J. 109. Heaney H. 182 341 342 343 362 444. Heasley G. E. 149. Heasley V.L. 149. Heaton B. T. 314. Hecht N. 511. Hecht S. S. 168. Hechtfischer S. 45 417. Hechtl W. 345 396. Hecker E. 417. Hecker H. 417. Heckl B. 308. Hedaya E. 173 347. Hefelfinger D. T. 350. Hefter H. 27. Hegarty A. F. 75 77 151. Hehre W. J. 66. Heiba E. I. 29 191 192. Heil H. F. 282. Heilbronner E. 367. Heim P. 243. Heimbach P. 306 320. Heimgartner H. 166 335. Heine H. G. 200. Heine H. W. 170. Heinrichs G. 380. Heinstein P. F. 538. Heinz G. 172. Heinzer J. 32. Heiszwol G. J. 134 135. Heitzer H. 447. Helbig R. 498. Helcke G. A. 19. Helgeson R. 177. Heller H. G. 356. Heller S. R. 493. Hellwinkel D. 36. Hemmer E. 423. Henbest H. B. 241 312. Henderson R. 57. Henderson T.470. Hendrick M. E. 356 392. Hendrickson J. B. 330 371 477. Hendry J. B. 94 95. Henglein A. 208,209,210. Henion J. D. 11. Hennig W. 520. Hennion G. F. 179. Henrici-Olive G. 318. Henrick C. A. 528. Henry R. A. 447. Henry-Basch E. 279. Henzel R. P. 158 400. Herb S. F. 530. Herbehold M. 308. Herberich G. E. 282. Herbert R. B. 555. Herdklotz J. K. 60 61. Herman D. L. 538. Heimanek S. 42 Herold C.-P. 452. Herr M. E. 38. Herr R. W. 264 276. Herries D. G. 496. Herrin J. 62. Herron D. K. 253. Hershey A. D. 490. Hershey J. W. B. 517. Hershman A. 322. Hertz H. S. 17. Herz W. 56 407 408. Herzog A. 512. Hess D. 156. Hess H. 287. Hess R. W. 322. Hesse G. 285. Hesse K.-D.452. Hesse M. 8 15 40 479 487. Hettche A. 301. Hettler H. 495. Hetzel F. W. 251. Heusler K. 450. Hevey R. C. 87. Hewerston W. 131 325. Hewitt D. G. 334. Hey D. H. 338. Hey H. 320. Hey J. E. 252. Heying T. L. 271. Heymes A. 41. Hiatt J. E. 122. Hiatt R. 186. Hickernell G. L. 40 459. Hickey M. J. 365. Hickinbottom W. J. 80. Hidai M. 310. Higa T. 439. Higgins R. J. 91. Hikino H. 16 430. Hikita T. 310. Hildesche J. 144. Hilfiker F. R. 374. Hill B. 320. Hill E. A. 73 113. Hill H. A. O. 564. Hill H. E. 429. Hill J. B. 174 383. Hill M. E. 267. Hilleman M. R. 507. Himowski R. J. 17. Hin B. C. 241. Hinderer H. 287. Hindle P. R. 25. Hindley J. 490 514 515. Hine J. 77.Hine R. 48. Hines L. F. 324. Hinjosa O. 28. Hintz P. J. 465. Hintzmann M. 202. Hirabayashi T. 288. 592 Author Index Hirai H. 314. Hiraoka H. 199. Hiraoka T. 414. Hirata N. 349. Hirata T. 404. Hirata Y.,412. Hiromoto Y. 198. Hirose Y. 412. Hirsch R. 170. Hirsh D. 508. Hirst J. 100. Hnoosh M. H. 32. Ho I. 145. Ho R. K. Y. 320,402. Ho Y. K. 546. Hoard J. L. 442. Hobbs C. W. 289. Hobson J. D. 348 482 487. Hochstetler A. R. 242. Hodder 0.J. R. 56 417. Hodgins. D. 565. Hodgkins J. E. 460. Horhammer L. 62. Horiger N. 430. Hoff E. F. 388. Hoffman L. 266 375. Hoffman M. K. 9 72. Hoffman M. Z. 215. Hoffman W. E. 253. Hoffmann J. 77 Hoffmann J. M. 461. Hoffmann R.37,153,156 169 172 315 370 Hoffmann R. W. 156,170. Hoffmann-Ostenhoff O. 573. Hoffsommer R. D. 526. Hofschneider P. H. 514. Hogan J. P. 31 1. Hogenkamp H. P. C. 493 558 561. Hogeveen H. 103 105 401. Hogg D. R. 89. Hoggett J. G. 90. Hohmann S. 31 1. Hohne E. 55. Hohnstedt L. F. 283. Hojo K. 381 463. Holbrook J. J. 568. Holburn R. R. 530. Holker J. S. E. 549 550. Hollaender J. 187. Holland J. M. 356. Holley R. W. 498 509. Holliman F. G. 555. Hollins R. A. 251 352. Hollis D. P. 506. Hollis M. L. 213 505. Holman R. J. 34. Holme D. 423. Holmes A. B. 349 355 464 465. Holmes J. L. 117. Holmes J. R. 20. Holroyd R. A. 212. Holton R. 477. Holtschmidt H. 448. Holub M.407. Holy A. 498. Hong C. I. 494. Hong-Yen Hsu. 41 7. Honjo M. 491. Honma S. 284. Hoogzand C. 398. Hook S. C. W. 27 284 305. Hoornaert G. 147. HOOZ,J. 285. Hope H. 55. Hopkins A. S. 205. Hopkins R. G. 395. Hopkinson A. C. 65. Hoppe B. 375. Hoppe D. 174. Hoppe I. 168. Hoppe W. 45 60 417. Hopper S. P. 280 290. Hordvik A. 448 449. Horeau A. 39,472. Horibe I. 407 409. Hormon I. 10. Horn D. E. 114. Horn D. H. S. 16,418. Hornby R. 263. Homer L. 232 234 235. Hornfeld Y.,502. Horng A. 244 285. Homing D. P. 81. Hornstra J. 62. Hornung V. 367. Horsfield A. 34. Horska K. 494. Hortmann A. G. 408,456. Horton D. 174. Horton H. 81 131. Hoshikawa H. 406. Hoskins J. A. 96.Hosokawa T. 402. Hosomi A. 189 294. Hough E. 15. Houghton L. E. 430 431. Houghton R. P. 79 263. Houk K. N. 158 162 163 348 389 391 463. House H. O. 33 245 259 328. Houser F. M. 55. Houser R. W. 439. Housman D. 518. Houssier C. 42. Hovey M. M. 255 285. Howard C. B. 33. Howard R. N. 318. Howarth T. T. 553. Howe G. R. 90 95 97. Howton D. R. 525. Hoy T. G. 46. Hoyes S. D. 528. Hrbek J. 39 472. Hruban L. 39 40 472. Hruska F. E. 496. Hseich R. S. 14. Hsieh K. 122. Hsu S. L. 372. Hub L. 268. Hubbard A. F. 281. Huber C. S. 55. Huber W. 525. Huberman J. A. 490. Hubert A. J. 306 446. Hudec J. 38 428 429. Hudnall P. M. 31. Hudson A. 20,22,27 189 227 280. Hudson H. R.39 11 1. Hudson R. F. 78 79. Huebner C. F. 363. Huennekens F. M. 558. Huper F. 468. Huet F. 279. Huttel R. 306. Huff L. 447. Huffman W. F. 379. Hufford C. D. 423. Hufnagel E. J. 30. Hug W. 37. Hughes L. D. 32. Hughes M. 511. Hughes N. W. 421. Hughes W. B. 316. Hui B. C. 310. Huisgen R. 160 170 266 345 396. Huisman H. O. 445 450. Hukins D. W. L. 506. Hummel C. F. 163. Hummel K. 317. Hummer B. E. 205. Hung J. G. C. 529. Hunt J. D. 250 288 332. Hunt J. W. 207. Hunter J. S. W. 524. Hunter N. R. 384. Hunter R. McD. 337. Hunter T. 518. Hunziker H. E. 196. Huoslef J. 62. Husain A. 216. Husband J. P. N. 268. Husk G. R. 290. Hussey A. S. 31 1. Husson H.-P. 428 483. Huston D.80. Hutchings M. G. 256,285. Author Index Hutchins J. E. C. 243. Hutchinson E. G. 376. Hutton J. 526. Huygens A. V. 332. Huyser E. S. 177 186. Huysmans W. G. B. 25. Hyer P. H. 428. Hylton T. A. 352. Hyman H. H. 30 267. Ibata T. 215. Ibers J. A. 53. Ibrahim B. 92. Ibuka T. 474. Ichihara A. 41 1. Ichikama I. 205. Ick J. 354. Iddon B. 444. Igarashi H. 420. Iguchi K. 421 422. Iguchi M. 412. Ihler G. 490 Ihn W. 254 434. Ihrig P. J. 361 437. Iida S. 493. Iitaka Y. 55 58. Ikeda S. 3 17 Ikeda Y. 310 Ikegami K. 333. Ikegami S. 385. Ikegami Y. 31. Ikehara M. 498. Ikemoto I. 48. Ilenda C. S. 146. Il’ina L. K. 300. Illingworth S. M. 273. Illurninatti G. 99.Imafuku K. 64. Imai K.-I. 491. Imai. S. 16. Irnamoto F. 518. Imamura A. 156. Imanaka T. 31 7 325. Irnhoff M. A, 126. Imjanctov N. S. 323. Imura N. 510. Inagami T. 496 Inarnoto N. 304 331. Inayama S. 56 407. Inglis R. P. 528. Ingold C. K. 36 63 271 Ingold K. U. 26 35. Ingram A. S. 188. Ingram V. M. 510. Inners L. D. 506. Innorta G. 7. Ino R. 430. Inoue I. 494. Inoue Y. 320. Inouye H. 406. Inouye Y. 167. Inskeep W. H. 37 496. Inubushi Y. 474. Inukai T. 320. Ioneda T. 524. Iowarone C. 99. Ipaktschi J. 355. Ippen K. 490. Iqbal M. Z. 313. Ireland R.E. 263 422. Irie H. 54 474 476 487 hie T. 116 412 Irngartinger H. 46. Irving P. 7. Irwin M. A. 407. Isaacs A. 507.Isaacs N. S. 117 157. Isaacs N. W. 50. Isaev V. L. 272. Isaks M. 84. Isaska S. 319. Isbell H. S. 452. Isenberg I. 521. Ishida K. 105. Ishida T. 407. Ishii H. 407. Ishii Y. 288. Ishikawa M. 293. Ishiza H. 83. Isida T. 300. Iskander Y. 136 Islam A. 479. Isono K. 493. Isoun M. 502. Ito K. 474 It6 S.,162. Ito T. 48. Itoh K. 288. Itoh M. 284. Ivan L. 35 Ivanov D. 272. Ivanov I. C. 469. Iversen P. E. 236. Iwaizumi M. 24. Iwamura H. 179 203. Iwamura M. 179 465. Iwasaki F. 48. Iwasaki K. 517. Iwasaki M. 23. Iwasaki S. 420. Iwashita Y. 319. Iwata R. 310. Iyer K. N. 55 485. Izawa K. 147. Jackman L. M. 65. Jackobs J. 51 453. Jackson A. H. 441. Jackson G. F. 302.Jackson J. L. 159 399. Jackson J. R. 439. Jackson R. 518. Jackson R. A. 20 153 272 280 294. Jackson W. R. 280 310 325 402. Jacobi P. 417. Jacobi V. 174. Jacobs-Lorena M. 518. Jacobson G. 560. Jacobson R. A, 475. Jacobus J. 179 243 327. Jacot-Guillarmod A. 278. Jacques J. 41 403. Jacquesy J.-C. 425 426. Jacquesy R. 425,426. Jakel W. 461. Jakle H. 359. Jaffe F. 274. Jagdale M. H. 79. Jagow R. H. 113. Jagt J. C. 260. Jain R. C. 14. Jain T. C. 409 410. JakovljeviC M. 190. James K. J. 469. Jamieson G. R. 523. Janda M. 230. Jandacek R. J. 44. Janion C. 505. Jankauskas K. J. 186. Jansing J. 157. Janssen J. F. 33 1. Janzen E. G. 22,23. Jardine A. 310. Jardine I. 242.Jarreau F. X. 481. Jarvie A. W. P. 295. Jasdorf B. 495. Jauffred R. 182. Jawdosiuk M. 100 340. Jay E. W. K. 486. Jean A. 281. Jeckel R. 568. Jeffcoat A. R. 469. Jefferies P. R. 540. Jeffrey E. A. 287. Jefford C. W. 173 370 373 385. Jeffrey G. A. 46 56 60. Jeffreys J. A. D. 54 55 321 478 487. Jeffries P. R. 417. Jeffs P. W. 55 379 477 478. Jeftic L. 224. Jeger O. 424. Jellinek T. 503. Jemison R. W. 327. Jencks W. P. 74 75 77 133. Jenell C. L. 116. Jenkins A. D. 298. Jenkins M. E. 303. Jenkins P. N. 15 474. Jennings B. H. 202 502. Jennings H. J. 452. Jennings K. 7. Jennings W. 320. Jennings W. B. 310 325 327. Jenny W. 351. Jensen E. Th. 233. Jensen L.A. 501. Jensen L. H. 49. Jensen T. C. 339. Jeppesen P. G. N. 490. Jeremic D. 190. Jerina D. M. 40 205 436. Jernow J. L. 112. Jesaitis R. G. 90 113. Jessop M. A. 443. Jewell C. L. 124. Jewett J. G. 113. Jibril A. 569. Jilyaeva T. I. 510. Jintal S. P. 138. Johne S.,467. Johns H. E. 501. Johns N. 554. Johns R. B. 503. Johns S. R. 475 478 486. Johnson A. W. 305 441 443 558. Johnson B. C. 560. Johnson C. D. 64,95 363. Johnson C. R. 264 266 276 375. Johnson G. S. 16. Johnson H. T. 300. Johnson J. R. 449. Johnson L. 550. Johnson L. N. 496. Johnson M. D. 130 265 288. Johnson M. G. 183 341. Johnson M. R. 122. Johnson N. 165. Johnson P. L. 51 449. Johnson R. A. 38. Johnson R.E. 243. Johnson S. M. 47 51 62 501. Johnson W. S. 252 268 528. Joines R. C. 173. Jolly P. W. 306 308. Joly M. 295. Jones A. J. 497. Jones D. G. 149. Jones D. N. 39. Jones D. W. 356 358. Jones (Sir) E. R.H. 425. Jones G. jun. 154 197 394. Jones G. H. 338 495. Jones J. B. 429. Jones J. G. Ll. 112 426. Jones K. W. 520. Jones L. B. 404. Jones M. 356 392. Jones M. jun. 173. Jones P. E. 94. Jones R.A. 303 440. Jones R. A. Y. 330 Jones V. K. 404. Jones W. M. 127 173. Jongejan H. 458. Jonkman L. 35. Jordan B. R. 51 1. Jordan T. H. 50. Jornvall H. 567. Josan J. S. 262. Jose F. L. 439. Joshi B. S. 21 1 479. Joule J. A, 468 469 479 483 484 486 487. Joullie M. M. 448.Jovanovich A. P. 124. Jubault M. 239. Judd. K. R. 92. Judson H. A. 165 183. Juenge E. C. 267 297. Juerges P. 202. Juers D. F. 166. Jukes A. E. 274 276 280. Julia M. 376. Juliani H. R. 432. Jung E. C. 505. Jung F. 256. Jurd L. 455. Jurkowitz D. 21. Just G. 428. Jutzi P. 292. Kaabak L. V. 301. Kabakoff D. S. 108. Kabalka G. W. 256 284. Kabayashi M. 105. Kabori N. 105 Kaeseberg C. 263. Kafatos F. C. 5 I 1. Kafka T. M. 529. Kagan E. C. 312. Kagan H. B. 157. Kagan J. 178. Kagawa S. 41 1. Kagawa T. 320. Kai K. 493. Kai Y. 287. Kaiser E. T. 32 87 152. Kaiser K. L. 340. Kajimoto T. 322. Kakehi A. 205. Kakihana T. 233 463. Author Index Kakisawa H. 417 421 422. Kakudo M.287. Kalfus K. 65. Kalischek A. 449. Kalman K. 96. Kalvoda J. 424. Kamai G. 305. Kamat V. N. 479. Kamata S. 416. Kamen R. I. 522. Kametani T. 472. Kamienski C. W. 275. Kamikawa T. 406. Kaminski W. 33. Kamiya M. 32. Kamiya T. 494. Kamprneier J. A. 182,341. Kan G. 174 205. Kandall C. 330. Kane G. J. 112 382. Kanematsu K. 205 348. Kanetsuma F. 531. KanKaanpera A. 69. Kanno T. 486,496. Kao J.-L. 381. Kapadia G. J. 471 545. Kapil R. S. 479. Kaplan B. H. 560. Kaplan E. R. 418. Kaplan J. P. 245. Kaplan L. A. 65 135 136. Kaplan M. S. 164 395. Kaplan N. O. 496 497 566 567 568. Kaptein R. 327. Karabatsos G. J. 104,559. Karady S. 12. Karasch M. S. 211. Karavan V.S. 436. Karavanov K. V. 300. Kariyone K. 250. Karle I. L. 48 53 56 58 59 486 501 502 566. Karle J. 53 56 59. Karlheinz L. 28. Karns T. K. B. 413. Karpeiskii M. Ya. 449. Karpi J. 127 128. Karpova E. N. 300. Kartha G. 62. Kasai N. 287. Kasai T. 522. Kashiwaga T. 183 184. Kaska W. C. 304 308. Kaski B. A. 55. Kasparet G. J. 89. Kastening B. 18. Katcha G. F. 266. Katchalsky A, 492. Kato H. 19. A uthor Index Kato M. 41 1. Ketter D. C. 323. Kato S. 204. Keulemans-Lebbink Kato T. 246 415 491. J. L. M. 167. Katoh M. 12. Keung E. C. H. 324. Katritzky A. R. 64 90 Kevan L. 177. 94 330. Keydar J. 515. Katz G. 509. Khalil M. F. 55 480. Katz T. J. 171 303 381. Khan M. A. 480. Katzenellenbogen J.A. Kan S. A, 81 83. 411. Khattak M. N. 58 501. Kauffmann T. 161 249 Khoo L. E. 178. 275 341. Khorana H. G. 490. Kawabata N. 266. Khuong-Huu Q. 426. Kawai M. 56 432. Kice J. L. 89 131 180. Kawajima I. 310. Kiefer E. F. 249. Kawakami J. H. 117 146 Kielbonia A. J. 137. 385. Kiener V. 307. Kawamoto K. 317. Kienle M. G. 541. Kawamura T. 19 33. Kienzle F. 180 250 288 Kawata M. 427. 332. Kawazu M. 494. Kier L. B. 8. Kearns D. R. 155 197. Kierkegaard P. 57 59. Keene J. P. 208. Kiers C. 35. Kehoe L. J. 323. Kieslich K. 425. Keiji Yamamoto 280. Kiguchi T. 476. Keizer V. G. 114 460. Kiji J. 320 401. Kelkar S. L. 479. Kilbourn B. T. 62. Keller L. S. 156 342. Kilbourn E. 436. Keller Sr. E. 32. Kilcast D. 3 1. Keller-Schierlein W.15. Kilko D. J. 138. Kellogg M. S. 201. Kim B. 156. Kellogg R. M. 162 177 Kim C. J. 110. 198. Kim C. S. 303. Kelly D. P. 65 66 102 Kim H. S. 46 56 60. 103 124 446. Kim J. B. 92. Kelly J. F. 157 163. Kim M. 266. Kelly R. B. 412 490. Kim Y.-H. 427. Kelm J. 3 1. Kimling H. 462. Kelsey D. R. 128. Kimpara K. 423. Kelso A. G. 182. Kimura B. Y. 305. Kemmitt R. D. W. 313. Kimura F. 508. Kemp D. S. 68. Kimura J. 491. Kemp T. J. 31 212. Kimura M. 427. Kende A. S. 163. Kindl H. 573. Kennard C. H. L. 50. King G. S. D. 47 446. Kennard O. 45. King J. C. 121. Kennedy J. P. 287. King J. F. 386. Kenner G. W. 492. King K. 374. Kensler T. T. 27. King R. B. 308 309 402. Kent M. E. 173 347. King R. J. 529. Kenyon D.H. 491. King T. J. 442. Kenyon R. S. 312. Kingsbury C. A. 64. Keppie S. A. 299. Kingston B. M. 273. Kerber R. C. 157 307 Kingston D. G. I. 11. 349. Kinnel R. B. 190. Kerr K. A. 45 46. Kinson P. L. 355. Kertesz J. C. 29. Kinstle T. H. 12 282 Kerwar S. S. 495. 361 437. Keske R. G. 32. Kirbach E. 299. Kessar S. V. 472. Kirby A. J. 81 83 100. Kessler H. 327 433. Kirby G. W. 451 554. Ketcham. R.. 449. Kirino Y. 28. Kirk D. N. 37 42 425. Kirkley R. K. 170 434. Kirkpatrick J. L. 109. Kirkwood S. 572. Kirman J. 301. Kirsanov A. V.,304. Kirsch S. 121. Kirschner S. 387. Kirson I. 432. Kirsonov D. N. 114. Kirst H. A. 41 1. Kiz Z. 40. Kischa K. 248. Kisic A. 528. Kislow K. 85. Kiso Y. 294 312. Kisselev L.L. 508 510. Kissinger P. T. 7. Kitahara Y. 163,246,343 347 391 415. Kitamura T. 347. Kitching W. 272,295,299. Kite G. F. 190. Kito N. 189. Kittleman E. T. 316. Kitzing R. 170 434. Klabunde K. J. 22 23. Klar R. 378. Klein A. 490. Klein H. A. 517. Klein J. 252 291. Kleinman R. W. 428. Klemmensen P. D. 178. Klemperer W. 365. Kleppe K. 490. Kleinar J. 77. KlimeS J. 412. Klingebiel U. I. 205. Klitgaard N. A. 453. Klooster H. 134. Kloosterziel H. 165 167 169 397 398. Klopman G. 79. Klopotova I. A. 3 11. Klose H. 309. Klosowski J. M. 293. Klumpp G. W. 263. Klundt 1. L. 330. Klyne W. 37 41 42. Knapp K. A. 349. Knauer B. R. 22 23. Knaus G. N. 175. Knauss L. 324.Knight D. C 422. Knight J. C. 430. Knipe A. C. 69 142. Knippers R. 490. Knoche H. 358. Knoess H. P. 279. Knorr R. 160. Knothe L. 349. Knox G. R. 314. Knox J. R. 414 540. Knunyants I. L. 137 281. Knutsson L. 140. Kobayakawa S. 242. Kobayashi A. 41 1. Kobayashi H. 45. Kobayashi M. 96 180 182. Kobayashi N. 55. Kobayashi S. 96 268 457. Kobett D. 49. Kobori N. 180 182. Kobuke Y. 158 390. Kobylecki R. J. 235. Koch C. W. 11. Koch E. 247. Koch H. F. 137. Koch H.-J. 425. Koch M. 482. Koch M. H. J. 59. Koch T. H. 375. Kocheshkov K. A. 298. Kochi J. K. 19 27 184 185 189 193 248. Kobrich G. 172 274 275 290 291 333. Koehl W. J. 191 192. Koehler H. 292. Kohler H.-J., 369.Koehler K. 74 I5 1. Koehn W. 154 388. Koekoek R. 567. Koelliker U. 525. Koeng F. R. 124. Konig J. 165. Koenigsberger R. 331. Koppelmann E. 161 275. Koerner von Gustorf E. 156. Kofron W. G. 139. Koga G. 175. Kogami K. 319. Kohara Y. 96. Kohen F. 427,428,430. Kohll C. F. 325. Kohnle J. F. 319. Kohno T. 518. Kohnte J. F. 323. Koizumi M. 472. Koizumi T. 12 80 85 302. Kolc J. 178. Kolesetskaya G. I. 135. Kolewa S. 304. Kolling 0. W. 305. Kollmar H. 172. Kollmeier H. J. 308. Kolodny N. H. 33 245. Kolomnikov I. S. 306. Kolor M. G. 432. Komarov N. V. 272. Kommandeur J. 35. Konde M. 511. Kondo M. 515. Kondo N. S. 506. Koningo R. N. H. 514. Konnert J. 58 501.Konz W. E. 170,345,396. Koo S. H. 546 547. Kooyman E. C. 332. Kopecky K. R. 187. Koptyug V. A. 102. Koreeda M. 16 430. Kornberg A. 490. Kornblum N. 114 266. Komprobst J. M. 220. Korsloot J. Q. 460. Korte W. D. 264 304 308. Koshland D. E. 557. Kosman D. 23. Kosower E. M. 568. Kostyuk A. S. 295. Kosuge T. 18 1. Kosugi H. 411. Koto K. 491. Kotz J. C. 283. Koubek E. 13 I. Koudijs A. 457. Kovacic P. 93 182 247. Kovacs C. K. J. 439. Kovacs J. 314. Kovar R. A. 277. Kovats E. Sz. 412. Kawazima I. 264. Koyama H. 54 62 487. Koziara A. 254. Kozima S. 300. Kozuka S. 12 96 183 184. Kramer D. M. 503. Kramer G. M. 104. Kramer J. G. 529. Kramer K. E. 248. Krampitz G. 491. Kranz E.304. Krapcho A. P. 114. Krasnova T. L. 293. Kraus A. 452. Kraus W. 243. Krause D. 502. Krebs A. 462. Kreevoy M. M. 243. Krefting I. 23. Kreilick R. 24. Kreiter C. G. 308. Krekels J. M. E. 397. Krepinsky J. 486. Kresge A. J. 65 95 137. Kress T. J. 450. Kretschmar H. C. 412. Krieger J. K. 92. Kroeger D. J. 135. Author Index Krohn K. 476. Kroll W. R. 311. Kronberger K. 33 245. Kronenberg M. E. 198. Kropp P. J. 204. Kroschwitz J. I. 366. Kroszczynski W. 552. Krow G. R. 204. Krsmanovic-Simie D. 504. Krubsack A. J. 439. Kriiger G. J. 24. Kriiger U. 202. Kriiger W. 453. Krueger W. C. 38. Kruger P. E. J. 478. Krull I. S. 412. Krusic P. J. 19 27 177. Krynitz U. 32. Ku T.32. Kubas G. J. 279. Kubieck D. H. 316. Kubinyi H. 417. Kubota T. 406. Kuc T. A. 310. Kuchen W. 300. Kuchitsu K. 373. Kucinski P. J. 124. Kuczkowski J. A. 346. Kudryavtsev R. V. 114. Kubbeler H.-K.,353. Kuehne M. E. 415,467. Kuntzel H. 222. Kuivila H. G. 292. Kulik S. 175 461 462. Kulkarni P. B. 405. Kulkarni S. V. 22. Kulsa P. 483. Kumada M. 189 293 294 3 12. Kumamoto T. 268. Kumanotani J. 319. Kumar A. 490. Kumari D. 421. Kummer D. 292. Kundu N. G. 75 151. Kunitake T. 71. Kuntsmann M. P. 412. Kunyants I. L. 272. Kunz F. 562. Kunze U. 297 299. Kuo C. H. 526. Kupchan S. M. 407 412 417,423,472,474,485. Kurabayashi M. 418. Kuran W. 287. Kureel S. P. 479. Kurichev V.A. 114. Kuriyama K. 409. Kurland C. G. 512. Kuroda H. 48. Kurosawa E. 412. Author Index Kuroso T. 87. Kurosowa H. 272 289. Kurtev B. J. 72. Kurtz J. L. 434. Kurz J. L. 129. Kurz M. 182. Kusame T. 498. Kusamran K. 16 532. Kuse T. 310. Kushi Y. 50. Kusunose M. 529. Kutney J. P. 483 543. Kuwajima I. 374. Kuwana T. 227. Kuwano M. 518. Kuwata K. 28. Kwan T. 20 28. Kwart H. 13 165 336 374 456. Kwee S. 239. Laarhoven W. H. 199. Labanauskas M. 509. La Barba N. 182. Labianca D. A. 187. Labonn S. 95. Lacave C. S. 524 529. Lacaze P. C. 23 1. Lachance A. 262. Lack R. E. 421. Lackashi J. A. 277. Lacombe L. 474. Lagercrantz C. 25 34 35. Lagerkvist U. 511.Lahournere J. C. 296. Lahti M. 69. Laine R. 292. Laird R. M. 88. Lakshmikantham M. 472. Lala L. K. 408. Lalancette J. M. 243 262 288. Lalizari I. 250. Lam L. K. M. 114. Lambert J. B. 124 302 369. Lamberton J. A. 475,478 486. Lamm B. 237. Lamola A. A. 502. Lamont A. M. 169. Lampman G. M. 368. Lampson G. P. 507. Lamvik A. 423. Lancaster J. E. 412 494. Lancelot C. J. 110 11I. Land E. J. 208 212 217. Landgraf W. C. 29. Landon M. 567. Landon W. 164. Lederberg J. 17. Lands W. E. M. 530. Lederer E. 524. Lane C. F. 255. Lednicer D. 443. Laneelle M. A. 524 529 Ledwith A. 172 205 348. 531. Lee A. G. 272. Laneelle G. 524. Lee A. L. 182. Langer E. 318 359. Lee C. C. 104 116. Langhoff C. A.59. Lee C. S. 520. Langley T. L. 567. Lee D. G. 64. Langlois N. 474. Lee H. A. 559 564. Langridge R. 509. Lee H. H. 178. Lansbury P. T. 374. Lee H. L. 472. Lapouyade P. 289. Lee J. B. 249. Lappert M. F. 272 273 Lee J. D. 52 301. 282 298 299 300 310. Lee J. R. 73. Lapporte S. J. 31 1. Lee S. L. 79. Larcombe B. E. 224. Lee W. S. 437. Larkins J. T. 97. Lee Y.-C. 297. LaRochelle R. W. 376 Leedy D. W. 227. 390. Leenhouts J. I. 62. Larock R. C. 244 285. Lee-Ruff E. 200,428. Larrabee R. B. 165. Leete E. 545 547. Larsen E. G. 560. Leeuwen P. W. N. M. Larsen J. W. 64 99 102 323. 339. Lefebre G. 3 17. Larson G. L. 12 280. Le Fevre P. H. 113. Larsson A. 561. Leffek K. T. 107. Larsson K. 61. Leffingwell J. C. 385 405. Lassman G.28. Leffler J. E. 184 282 Last A. M. 71. 436. Lastity D. 510 51 1. Leftin J. H. 13. Lastoniwsky R. R. 248. Legendecker F. 257. Latomy J. 65. Le Goff E. 444 461. Lattes A. 255. Legrand M. 36. Lau P. W. 20. Le Grand S. O. 386. Launay J. P. 233. Legzdins P. 310. Laurent A. 220 229. Lehane D. P. 524. Laurent-Dieuzeide E. 220. Lehman D. D. 241 311. Laurie V. W. 368. Lehman K. 454. Lavie D. 419 432. Lehmkuhl H. 278 286 Lavielle G. 304. 319. Laviron E. 239. Lehn J. M. 433 465. Lawesson S.-O.,178. Lehnert W. 262. Lawless J. G. 233. Leibfritz D. 433. Lawlor J. M. 8 1. Leicht C. L. 379. Lawrence R. V. 313. Leichter L. M. 155 394. Lawrie W. 419. Lein B. I. 319. Lawson A. 448. Leiserowitz L. 46. Lawson A. J. 91. Leitch J.156. Lawson D. F. 33. Leitch L. C. 11. Lawson J. 46. Le Men J. 428. Lawson J. A. 464. Lemmer F. 45. Layer R. W. 35. Lemmers J. W. F. M. Lazzaroni R. 324. 323. Leaffer M. A. 525. Lemmon R. M. 491. Leardini R. 181. Lenchte W. 319. Leaver D. 443. Lengyel I. 12 14. Leaver I. H. 34. Lengyel P. 517. Lebedev S. A. 292. Leniart D. S. 33. Le Bel N. A. 446. Le Noble W. J. 109. Lebrun H. 19. Lentz P. J. 567. Leclercq J. 15 43 1. Leonard D. R. A. 31. Leonard N. J. 162 463 492 50 1. Le Patourel G. N. T. 406 537. L’Eplattenier F. 322. Lepley A. R. 179. Lequan M. 281. Le Quesne P. 483. Lergier W. 14. Leriverend P. 253 377. Lesbre M. 295. Leser E. G. 341. Leshcheva A. I. 317. Leskovac V. 568. Leskovac W.568. Lessard J. 255. Lessard U. 150. Letcher R. 15 474. Letsinger R. L. 199 495. Leung F. 51 449. Leusink A. J. 298 306. Levanon H. 28. Leverson L. L. 80. Levi E. M. 247. Levin C. 107. Levina E. S. 510 51 1. Levinthal C. 51 1. Levisalles J. 278,425,426. Levison J. J. 313. Levitin I. 243. Levitt M. 508. Levitt T. E. 260. Levy A. 569. Levy A. B. 149. Levy E. C. 419. Levy G. C. 64. Levy H. B. 507. Levy M. 360. Lewandosa T. 239. Lewh B. 489. Lewis A. 90 95. Lewis F. D. 200. Lewis J. B. 512. Lewis J. W. E. 22. Lewis P. M. E. 65. Lewis R. A. 302. Ley S. V. 362. Leyendecker F. 379. L’Her M. 240. Lhomme J. 409. Lhomme M. F. 417. Li G. S. H.. 244. Li J. P. 144. Li T.. 252.Lichtenthaler F. W. 452. Lichtin N. N. 215. Liebman S. A. 21. Liechte R. R. 87. Liehr J. G. 303. Lie Ken Jie. M. 525 533. Liepa A. J. 441. Lifshitz C. 7. Lifson S. 371. Liggero S. H. 114. Light J. R. C. 278 287. Light R. J. 524 531. Lijima I. 486. Lilley D. M. J. 106. Lillicrap S. C. 217. Lillie J. 208. Lillien I. 123. Lillya C. P. 110. Lin S.-Y. 521. Lin W. C. 20. Lin Y. 117 120. Linda P. 94. Lindberg J. G. 277. Linde H. H. A. 430. Lindemann J. 507. Lindley P. F. 307 309. Lindner E. 297 299 309. Lindner H. J. 47. Lindner R. E. 97. Lindsay G. 407. Linek A. 407. Ling A. C. 97. Ling N. C. 55 431 480 482. Lingens F. 493. Lingier W. R. F. 446. Lingquist L. 574. Linzina 0.V.279. Lipinski C. A. 263. Lipkin A. H. 469. Lipscomb W. N. 57. Lisewski R. 502. Liston A. J. 428. Listowsky I. 41. Litchfield C. 523. Litt A. D. 196. Litt M. 510. Littlewood P. S. 430. Litzow M. R. 282. Liu C. Y. 116. Liu H. J. 384 469. Liu K.-T. 117 143 146 385. Liu R. S. H. 198 204. Liu S. J. 287. Livi O. 418. Livingston D. C. 300. Livingston R. 20 23 28 212. Lloyd D. J. 142. Lloyd H. A. 14 467. Lloyd J. P. 308. Lloyd R. V. 18. Lockart R. Z. 508. Lockhart J. C. 271. Lock Lim Chan. 274. Lodish H. F. 515 517 518. LofRer H. P. 160 280. 387. Author Index Loew P. 252 406 528 536. Loewenstein R. M. J. 347. Loewus F. A. 573. Login R. B. 362. Lohse C. 205. Lokensgard J.32. Lom,L.K. M. 110 111. Loman H. 214. Lomax A. 21 224. Long G. G. 305. Long L.,jun. 56. Longeray R. 357. Longone D. T. 155 345 350 375. Longridge R. 57. Lora-Tomayo M. 447. Lorenc Lj. 41 428. Loridan G. 182. Lossing F. P. 347. Loudet M. 370. Loudon A. G. 9. Louis J. B. 79. Loukas S. L. 110. Lourn J. W. 149. Loustalot F. 370. Lowe L. A. 473. Lown J. W. 254 345,433 434. Lucas M. 63. Luche J. L. 157. Luckhurst G. R. 18 21 177. Luddy F. E. 530. Ludowieg J. 569. Ludt R. E. 274. Ludwig P. K. 196. Luning B. 468. Luttke W. 433. Lui S. J. 62. Luisi P. L. 569. Lukacs G. 429. Lukevits E. Ya. 271. Lukina M. Yu. 384. Lumbantobing T. 441. Lunazzi L. 21 31. Lund H. 233 236 239 440.Lundeen A. J. 287. Lunn W. H. 387. Lunney D. 33. Lura R. D. 155. Lusinchi X. 429. Luskus L. J. 163,391,463. Lustgarten R. K. 115 116. Luth H. 289. Lutsenko 1. F. 295. Lutz F. E. 249. Lyakhavekskii Yu. 114. Lyall J. M. 428. Lyle R. L. 123. Author Index Lynen F. 535 553. Lyons A. R. 287. Lythgoe B. 430. Mabry T. J. 407 408 455. McAdoo D. J. 10 173. MacAlpine G. A. 384. Macaulay E. W. 62 424. McCabe P. H. 414. McCain D. C. 24. McCall J. M. 166. McCart P. D. 150. McCarthy B. J. 506. McCarthy J. P. 163 460. McCarty C. T. 342 444. McCaully R. J. 268. McCay I. W. 158 379 396. Macchia B. 403. Macchia F. 403. McCloskey J. A. 497,533. McCloskey J. E. 409,410. McClure D.E. 193. McClure R. J. 56 474. McClusky J. G. 482. Maccoll A. 9. McCombs D. A. 135 168. McComsey H. J. 240. MacConaill R. J. 448. McConnell A. A. 35. McConnell B. 493. MacConnell J. G. 531. McCormick J. P. 41 1 528. McCrae W. 529. McCredie R. S. 501. McCrindle R. 414. McCullough J. J. 198. McDaniel D. M. 155. McDonagh A. F. 441. McDonald E. C. 403. McDonald J. 492. Macdonald P. L. 41 1. McDonald W. S. 286. McDowell J. J. H. 61. MacEwan A. W. 59. McFarlane N. R. 98 339. McGhie J. F. 421 422. McGillivray D. 117. McGillivray G. 250 529. McGinty D. J. 29. MacGregor R. A. 315. McGuire J. S. 571. Machacek V. 91. Machat R. 159. Machattie L. 490. Machida Y. 413. Machiguchi T. 347.McIntosh J. M. 205. Mack K. E. 266. McKague B. 483. Mackay D. 182. Mackay I. R. 48. MacKay W. D. 528. MacKeller F. A. 493. McKellop T. F. 90. McKenly S. V. 102. Mackenzie J. S. 20. Mackenzie K. 367. Mackenzie R. K. 328. McKeown J. M. 549. McKervey M. A. 114 190 191 373 382 402 408. Mackie A. G. 317. McKillivray G. 288. McKillop A. 180 250 265 268 272 288 332 374. McKillop T. F. W. 204. McKinley S. V. 328. McLafferty F. W. 7 10 17. McLauchlan K. A. 23. McLaughlin G. M. 287. Maclean D. B. 11 14,473 546. McLean J. 419. McLean S. 479. MacLeod J. K. 455. McLoughlin T. E. 107. McMahon D. M. 72. McMillan M. 23. McMullen J. C. 283. McNally D. 365. McNamara P. M. 282. McNaught R.P. 432. McNaughton G. S. 215. MacNicol D. D. 53 221 328 374. McPhail A. T. 53 55 56 302 477. McPherson A. 497 567. McPherson C. A. 145. McQuilkin R. M. 355. McQuillin F. J. 16 242 310 320 532. McTigue P. T. 83. McWilliams D. 18. Madan V. 437. Madison J. T. 498. Maeno T. 7. Maercker A. 263 278. Maerker G. 529. Mageswaran S. 327. Magomedov G. K. 325. Magrath D. I. 494. Mague J. T. 318. Maher V. M. 521. Mai H. N. 474. Maier G. 375. Maier N. A. 281. Maier W. 543. Maillard A. 249. Main P. 413. Maire J. C. 299. Maitland D. J. 337. Maitlis P. M. 318 340. Majeste R. 52. Mak T. C. W. 50. Makarova L. G. 27 1. Makishima S. 314. Makor A. 205. Makosza M. 100 340. Makovetskii K.L. 317 319. Malatesta V. 178. Malcolm A. D. B. 568. Malek B. A. 70. Malek J. 242. Malinoski G. L. jun. 24. Malisch W. 296. Malkins H. 109. Malkus H. 31. Malley T. P. 107. Mallory F. B. 172. Malone G. R. 459. Malone J. F. 286. Maloney T. W. 345. Malpass J. R.,204 387. Malstrom L. 551. Mamantov A. 173. Mammi M. 50. Manassen J. 315. Manchand P. S. 418. Mancini V. 340. Mandelbaum A. 13. Mandville G. 257 379. Manery E. L. 182. Mangia A. 46. Mangini A. 21 31. Mango F. D. 157 400. Mangold H. K. 529. Manhas M. S. 14 438. Mani I. 21 1. Manion M. 73 113. Manley S. A, 370. Mann B. E. 313. Mann C. K. 228 229 238 240. Mann F. G. 273. Mann G. 369. Mann J. 406 531 537. Manor H. 518.Mansell C. M. 321. Manske R. H. F. 467 473. Marcker K. A. 508 518. Marcoux L. S. 2 1 224. Mardell B. 252. Margoliu Z. 68. Margulis T. N. 427. Marino G. 94 96 97 340. Marino M. L. 476. Markert J. 156. Markgraf J. H. 11. Markham K. R. 455. Marko L. 314. Markovits J. 531. Marner 0.A. 347. Marples 9. A. 112 182 341 342 426. Marquisee N. 498. Marr G. 130. Marsh G. 197. Marsh P. G. 247. Marsh R. E. 58. Marshall J. A. 242 253 259 285 379 41 1. Marshall J. L. 260 370. Marsi K. L. 86 302 303. Marsili A. 252 421. Martens D. 134 168. Martens H. 147. Marten-Smith M. 90. Martin A. 414. Martin J. C. 109. Martin J. J. 374. Martin K. A. 149. Martin K. R. 276. Martin M. M. 531.Martin R. G. 518. Martinet P. 238. Martinez A. G. 126. Martinez-Carrera S.,46. Martini T. 160. Marton J. 328. Martynov B. I. 137 281. Marumo F. 45. Marumo S. 40. Maruyama K. 21. Maruyama M. 423. Maruyama T. 29. Marvell E. N. 253 377. Marvin D. A. 490. Marx J. N. 405. Maryik R. M. 319 321. Masaki N. 54 487. Masamune S. 159 242 381 463. Masaracchia J. 154. 388. Maskens K. 16 531 532. Maslen E. N. 46. Mason K. G. 343. Mason S. A. 49. Mason S. F. 36. Masse B. 493. Masse J. 42. Masse J. P. 292. Massey A. G. 272 344. Massingill J. L. 460. Massol M. 294. Massolo G. 100 126. Masuda T. 491. Masui K. 320 401. Mateescu G. D. 101,102. Mathew C. P. 455. Mathew M. 61. Mathews 9. W.57. Mathias A. P. 496. Mathieson A. McL. 43. Matlin S. A. 247. Matsubara T. 530. Matsui K. 67 200. Matsui M. 404 410 411 414 416 469. Matsumoto K. 434. Matsumoto T. 41 1 417. Matsumura H. 64. Matsumura N. 247. Matsuo A. 407. Matsuoka T. 16 350. Matsuura T. 56 198 204 334 403 404 407 432. Matta K. L. 41 1. Mattern G. 43 1. Matteson D. S. 272 280. Matthews 9. W. 201. Matthews J. S. 323. Matthews R. S. 428. Mattocks A. R. 468. Matyukhina L. G. 417. Matz M. J. 417. Matzura H. 344. Maurin R. 123 406. Mauzerall D. H. 572. Mawdsley E. A. 305. Maxfield P. L. 319. Maxwell A. F. 20. Maxwell C. R. 571. Mayer C. F. 406. Mazaitis A. J. 522. Mazerolles P. M. 295. Mazhar-U1-Haque 52 56 301 407.Mazur S. 155 204 440. Mazza F. 49. Mazza M. 548. Mead W. L. 14. Meakins G. D. 425 428. Meares C. F. 31. Meehan G. V. 361. Meeks B. S. 265. Mehta G. 409. Meiboom S. 368. Meinema H. A. 305. Meinwald J. 204 427. Meisinger R. H. 204. Meistrich M. L. 504. Melamed M. D. 567. Melby L. R. 498. Melent’eva T. A. 441. Meleshevich A. P. 177. Melicharek M. 227. Melillo D. G. 159 331 390. Mella K. 568. Author Index Mellor J. M. 192. Mel’nichenko L. S. 298. Melo A. 574. Mels S. J. 232 236. Melvin L. S. jun. 405. Memory J. D. 83. Menapace H. R. 3 16. Mendenhall G. D. 247. Meney T. 427. Menger F. M. 64 71 75 152. Mengharth K. 96. Merecek J. F. 83. Merenyi R. 446. Merigan T. C. 490 508.Merlini L. 479. Merril C. R. 500. Merrill S. H. 498. Merritt M. V. 25 239. Merstrich M. L. 502. Mervyn L. 558. Mersereau M. 312 429. Mestres R. 12. Metcalfe J. 169 397. Meth-Cohn O. 444. Metras F. 370. Metzger J. 182. Metzler D. E. 572. Meyer J. W. 199. Meyer K. 430. Meyer W. E. 494. Meyerhoffer A. 61. Meyers A. I. 255 261 459. Meyers C. L. 22. Meyers J. A. 173. Meyers M. 48. Meyerson S.,11 104 182. Meyerstein D. 21 1. Meyer zu Reckendorf W. 452. Miao C. K. 529. Michael B. D. 209 215 217. Michaelis P. 202. Michalke H. 504. Michel G. 531. Michniewicz J. 498. Michnowicz J. 14. Michon V. 65. Middleton E. J. 16. Middleton S. 305. Midgley J. M. 62 424. Miginiac P. 263.MihailoviC M. Lj. 41 190 428. Mikhailov 9. M. 272. Mikhlina E. E. 330. Mikolajczak K. L. 532. Mildvan A. S. 570. Mile B. 18 26 177. Miles D. W. 37 496. Author Index 601 Milikian A. P. 179. Millar D. B. S. 506. Millar P. G. 234. Miller B. 164 334 337. Miller D. S. 282. Miller J. 98 182. Miller J. M. 305. Miller L. L. 205. Miller N. E. 283. Miller 0. L. 518. Miller R. G. 314. Miller S. A. 65 136. Miller W. L. 542. Miller W. M. 495. Mills H. H. 53. Mills 0. S. 307 309. Milne G. 548. Milne G. M. 264. Milne G. W. A. 14 467. Milovanovic J. 183. Milstein J. B. 42. Milstein S. 69 558. Minato H. 96 105 180 182 407 409. Mincione E. 268. hdinghetti G. 281 308. Minisci F. 178.Minnikin D. E. 16 532. Minobe M. 48. Miotti U. 143. Mironov V. F. 287. Mirrington R. N. 130 268 41 1. Mirzabekov A. D. 510 511. Misaki A. 531. Mishima H. 418. Mislow K. 38 302 305. Misoguchi T. 494. Misono A. 310. Misra D. N. 520. Misra R. 437. Misumi S. 350 355. Mitchell D. K. 304 308. Mitchell R. H. 251 303 351 352. Mitchell R. W. 310. Mitchell S. 35. Mitchell T. R. B. 241 31 1 312. Mitnick M. A. 238. Mitsui Y.,58. Mitsunabu O. 491. Miura A. 493. Miura I. 179. Miura T. 427. Miyakoshi H. 417. Miyanishi T. 300. Miyazaki M. 508. Mizutani S. 489 515. Mizutani T. 487. Mhala M. M. 79. Moats W. L. 52. Mochizuki F. 242. Mock W. L. 171,256. Mobius K. 31 33. Moedritzer K.27 1. Monnighoff H. 445. Moffat A. J. 316. Moffat J. 318. Moffat J. G. 493 495. Moffit W. 37. Mol J. C. 316. Mole T. 271 287. Molin Yu N. 21. Mollier Y.,449. Mollov N. M. 469. Monahan M. W. 145. Mondelli R. 479. Mondon A. 476. Mondt J. L. 251 351. Moness D. D. 127. Money T. 553. Monier R. 51 1. Moniz W. B. 65 135 136. Monneret C. 426. Monroe B. M. 26. Montando G. 328. Monti H. 390. Monti L. 403. Monti S. A. 368. Monton G. O. 15. Montrozier H. L. 524. Monvernay A. 231. Moodie R. B. 64 78 90. Moore D. W. 49 50 447. Moore H. W. 334 436. Moore J. S. 216 530. Moore M. 497. Moore W. R. 156 174 275 383 385. Moorhouse S. 299. Morand P. 428. Moreau Cl. 336. Moreau J. 263. Morelli I.252 421. More O’Ferrall R. A. 141. Moretti I. 42. Morgan B. A. 360. Morgan G. L. 272 277. Mori K. 404 410 411 414 416. Mori T. 200. Moriarty R. M. 427. Moriconi E. J. 157 163. Morikawa N. 518. Morino Y. 373. Morisaki N. 412. Morita K. 457. Moritani I. 333 402. Moritz A. G. 98. Moriwaki M. 167. Morley J. R. 249. Morrell M. L. 26. Morris D. G. 121. Morris J. 518. Morrison A. 529. Morrison G. A. 13. Morrison G. F. 285. Morrison J. D. 264. Morrison W. H. 256 291. Morrison W. R. 523. Morse D. E. 518. Morton D. R. 200. Morton G. O. 412 459 494. Morton I. M. 16. Morton J. R. 35. Moscowitz A. 37. Mose W. P. 41. Moser J. P. 433. Moser W. R. 156 275 385. Mosher H. S. 41 268.Mosimann J. E. 500. Mosnaim A. D. 93. Moss G. P. 40. Moss R. A. 173 428. Mosteller R. 518. Motes J. M. 137. Motitschke L. 465. Motl O. 14. Motoki S. 257. Mottus E. H. 230 Mourkides G. A. 569 Mowat W. 273 310. Mowery P. C. 90. Mozulenko L. 102. Muck D. L. 219. Muhlstadt M. 369. Mueller D. C. 280 302. Muller E. 318 359. Muller J. 308. Muller P. 383. Mueller R. A. 379. Muller-Warmuth W. 24. Muller-Westerhoff U. 347. Muhn H. 359. Muich M. J. 68. Muir C. N. 426. Muirhead H. 57. Muirhead J. S. 30. Mukai F. 493. Mukai T. 170 202. Mukaiyama T. 268. Mulder J. J. C. 153. Mulheirn L. J. 541 549 550. Muller H. 35. Muller-Hill B. 521. Munday K. A, 571. Mundy D. 39 428. Mungell W.S. 495. Munns A. R. I. 58. Munson B. 14. Murahashi S. I. 346. Murakami K. 21. Murakami M. 508. Murakami Y. 83. Murao K. 498. Murata E. 16. Murata I. 163 363 391. Murayama W. 58. Murphy C. V. 132. Murphy G. P. 553. Murphy S. 558. Murphy W. S. 163 460. Murr 9. L. 118. Murray D. G. 479. Murray H. C. 38. Murray R. D. H. 414. Murray R. K. 302. Musajo L. 503. Musgrave 0.C. 197 283 358. Musker W. K. 12. Musso H. 160 281. M uszynski J . 28 7. Myers A. M. 67. Myers J. D. 170. Myers L.S.,213,214,505. Naegeli P. 41 1 412. Nagahori H. 418. Nagai T. 7. Nagashima N. 58. Nagata W. 416 429. Nagendrappa G. 379. Nagura T. 494. Nahringbauer I. 53. Naidoo B. 543. Naidu K.418. Nair M. K. V. 31. Naito T. 476. Nakagawa C. S. 196. Nakagawa Y. 16. Nakahara Y. 414. Nakai M. 336. Nakajo K. 257. Nakama S. 64. Nakamaye K. L. 319. Nakamura M. 407. Nakamura N. 116. Nakane R. 331. Nakanishi K. 16 40 430. Nakanisi Y. 368. Nakatani Y. 417. Nakao Y. 33. Nakashima R. 432. Nakatsuji H. 19. Nakatsuka N. 159. Nakayama H. 504. Nakayama J. 181 244 266 340. Nakazawa T. 363. Namanworth E. 108. Nambu H. 260,285. Nanbata J. 493. Narang R. S. 205. Narang S. 501. Narang S. A. 498. Narasimh Acharya P. V. 531. Narasimhan N. S. 479. Narayanan C. S. 438. Narayanaswami S. 472. Narisada M. 414 416. Nasini G. 479. Nathan E. C. 101. Nathan G. W. 404. Natori S. 359 421.Natsubori A. 331. Natta G. 320. Naudet M. 525 528. Naur T. A. 152. Nawaral J. 524 532. Nayak U. R. 408. Neal G. T. 31. Nebzydoski J. W. 119. Neckers D. C. 177. Needham L. L. 360. Neeff W. R.,301. Neet K. E. 557. Negishi E. 265 285. Negoro T. 96. Neilson T. 497. Neirnan L. A. 180. Nekrasov Yu. S. 180. Nelsestuen G. L. 572. Nelson D. R. 531. Nelson G. L. 165 395. Nelson J. A. 415. Nelson R. F. 227 233. Nelson S. F. 465. Nelson V. R. 483 543. Nemes N. M. 507. Nenitzescu C. D. 361. Nery R. 492. Nesmeyanov A. N. 281 325. Nesmeyanova 0.A. 384. NeSoviC H. 41 428. Nestler G. 248. Neta P. 19 28 211 215. Neugebauer F. A. 22 31 25. Neuhahn H.-J. 14. Neuman R. C. 188. Neumann H. 262.Neumann H. M. 278. Neumann P. 351 465. Neumann R. M. 365. Neumann W. P. 187 271. Neunhoeffer H. 465. Author Index Neville-Jones D. 428. Newall C. E. 267 429. Newbould J. 422. Newman M. S. 251 293 335 436. Newton M. G. 54 55 485. Niazi G. A. 447. Nibbering N. M. M. 11 12. Nicely V. A. 245 465. Nichol A. W. 441. Nicholas K. 280. Nichols J. D. 115 116. Nichols J. L. 512. Nicholson J. M. 97 181. Nicholson K. 325. Nickon A. 117 120. Nicolau C. 29. Nicolson J. M. 77. Niebch U. 490. Niehaus W. G. jun. 528. Nielsen J. 398. Nienhouse E. J. 374. Nilsson T. 25. Ninomiya I. 476. Nirva M. 412. Nishida T. 40 179. Nishikawa M. 196. Nishimoto T. 504. Nishimura M. 407. Nishimura S. 242 508.Nishinaga A. 334. Nishitani Y. 476. Nishiwaki T. 434. Nishiyama A. 412. Nisuiguchi I. 190. Nitta I. 67. Nivard R. J. F. 199. Nixon J. F. 273. Niznik G. E. 256 291 Noda M. 404. Noth H. 272 302. Nogradi M. 328. Nojiri T. 96. Noller H. F. 567. Noltes J. G. 297,298,305 306. Nomoto K. 16 430. Nonhebel D. C. 93. Nordlander J. E. 138. Norman R. 0. C. 18 20 23,29,96 139 188 192. Norrestam P. 59. North B. E. 399. Northolt M. G. 51. Norton D. A. 62. Norton J. R. 33. Norton K. B. 421. Nounou P.,10. Novak C. 407. Novikova N. V. 281. Author Index Nowacki W. 54. Nowak E. N. 103. Nowakowski J. 19. Noyce D. S. 67. Noyori R. 258 401 525. Nozaki H. 200 368 444. Nozoe S.412 413. Nozoe T. 139. Nozu K. 504. N.-T. Luong Thi. 3 10. Niirnberg R. 341. Nurayanan P. 60. Nussey B. 11. Nyberg K. 225. Nyburg S. C. 51 286 449 501. Nyholm (Sir) R. S. 325. Oae S. 12 87 89 96 142 143 183 184 336. Oakenfull D. G. 71 75 82. Oakes J. 33. O’Bara E. J. 94 330. Obata N. 345. Oberhansli W. E. 55. Obeshchalova N. V. 317. O’Brian D. H. 66. O’Brien D. H. 295. O’Brien E. J. 59. O’Brien R. E. 248. O’Brien R. J. 286. Ochai E.-I. 314. Ochiai M. 457. Ochoa S. 517. Ochrymowycz L. A. 12 33. O’Conner K. 339. O’Connor C. J. 149. Oda K. 54 487. Oda M. 343. Oda R. 190 23 I 345. Odagi T. 401. Odell B. G. 156 159. O’Dell C. A. 495. Odham G. 527. Odom J. E. 271. O’Donnell J.H. 208. Ofele K. 308. Oehlschlager A. C. 170 287 323. Offhaus E. 307. Ogasawara K. 483. Ogata I. 310. Ogata Y. 94 96. Ogiso A. 418. Ogston A. G. 490. Ogunlana E. O. 544. Ogura K. 198. Ohashi Y.,45. Ohki M. 404 41 1. Ohloff G. 166,410,411. Ohnishi Y. 12. Ohno A. 12 189. Ohno K. 54 306 487. Ohno M. 460. Ohta H. 178. Ohtsru M. 409. Ohtsuka E. 490 498. Ohtsuka N. 336. Oine T. 202 494. Ojeda M. 63. Ojha N. D. 437. Okada A. 198. Okamoto K. 67. Okamoto T. 322 522. Okamura W. H. 162. Okawara R. 272 289. Okaya Y. 621. Okazaki M. 363. Okazaki R. 185 331. O’Keefe J. H. 312. Okigawa M. 406. Okinoshima H. 293. Okorie D. A. 423 424. Okuda S. 420. Okuda T. 57. Okumura K.494. Okumura T. 429. Okuno T. 417. Okupo S. 504. Okuyama T. 147. Olah G. A. 66 96 101 102 103 104 116 124 446. Ol’dekop Y.A. 281. Oldham P. H. 182 338. Olin S. S. 153 204. Olive S. 318. Oliver L. K. 481. Oliver J. P. 272 279 286. Oliver W. R. 12. Ollis W. D. 167 327 328 332. Olmstead H. D. 259. Olofsson B. 225. Olsen A. H. 426. Olson J. O. 547. O’Malley R. M. 7. O’Neal H. E. 155. Ono Y. 323. Onsager 0.-T. 3 17. Oosterhof L.-J. 153 327. Oparin A. I. 49 1. Orahovats A. 369. Oram R. K. 301. Organ T. D. 245 427. Orlando C.-M. 334. Ormand K. L. 332. Oro J. 53 1. Orr J. C. 312 429. Ort M. R. 230. Orvik J. A. 99 338. Orwig B. A. 246 268. Orzech C. E. 104. Osaki K. 54 56 57 487.Osawa E. 382. Osband J. A. 419. Osborn C. L. 154 388. Osborn J. A. 241 310. Osborn T. W. 162. Osserman E. F. 57. Ossip P. S. 85 302. Osterman G. 179 327. Oth J. F. M. 101 328 354 372 398. Ottinger R.,370. Ouchi M. D. 247. Ouellette R. J. 107. Ourisson G. 409 417 431. Ovadia J. 216. Overberger C. G. 187 460. Overmayer R. G. 125. Overton K. H. 407 413. Owston P. G. 62. Ozainne M. 410. Ozawa T. 28. Pace N. R. 51 1. Pachaly P. 417. Pacifici J. G. 35. Paddon-Row M. H. 152. Padovan M. 143. Padwa A. 122 154 388. Paecht-Horowitz M.,492. Paetzold P. I. 282. Pagano A. H. 188,248. Page G. 246. Page M. I. 74. Page S. W. 485. Pagni R. 138. Pagnoni U. M. 418. Pahari M. 129. Pahk M.J. 204. Pai B. R. 470 472. Paiaro G. 324. Pais M. 48 1. Paik C. H. 181 338. Pailer M. 468. Paioni R. 351. Palazzo G. 11 1. Palenik G. J. 61 62 473. Palm D. 569. Palmer K. J. 158 316 400. Palmer P. 491. Panattoni C. 301. Panchartek J. 91. Pandell A. J. 192. Pandit U. K. 558. Panke D. 56. Pant B. C. 299. Panunzi A.. 324. Pao Y. H. 38. Paul K. 68. Paolella N. 428. Pauling P.,60. Papa R. 107. Paulissen R. 255. Pape H. 574. Paulsen H. 452. Pappiaonnou C. G. 183. Paulus E. F. 49. Paquette L. A, 132 133 Pauson P. L. 314 321. 154 155 157 158 160 Pavanararn S. K. 530. 164 170 204 233 316 Pavlik J. W. 361. 361 362 387 394 395 Pawelkiewicz J. 560. 397 399 400 437 439 Pawley G. S. 5 1. 463. Pawson B.A. 41 1. Paradies H. H. 57. Pawson R. J. 254. Paradkhar M. V. 479. Payne T. G. 536. Park J. H. 566. Payne T. J. 417. Parker A. J. 141 142. Peachey S. J. 300. Parker D. J. 569. Peake B. M. 31. Parker D. M. 300. Pearce P. J. 263 275. Parker V. D. 226. Pearson D. W. 148. Parker W. 57 112 374 Pearson E. F. 42. 386. Pearson J. M. 360. Parkin J. E. 424. Pearson R. G. 315. Parkin J. G. 222. Pecci G. 240. Parks J. E. 117. Peddle G. J. D. 298 300. Parrish F. W. 452. Pedersen A. O. 178. Parrott J. C. 289. Pedersen C. J. 269 465. Parry D. R. 552. Pedler A. E. 227. Parry F. H. 388. Pedley J. B. 282. Parshall G. W. 306 333. Pedone C. 44. Parsons P. G. 542. Pedulli G. F. 2 1 31. Partch R. E. 190. Peiren M. A. 446. Parthasarathy R.52. Pekel N. D. 441. Pascard-Billy C. 407. Pelichet C. 322. Pashchenko N. M. 317. Pelizzi G. 46. Pastan I. 522. Pelizzoni F. 418. Pasto D. J. 369. Pellegrini M. M. 182. Pastra S. C. 202 502. Pellerito L. 289. Pasynkiewicz S. 287. Pelletier S. W. 54 55,467 Patai S. 149. 485. Pataki L. 130. Pelter A. 256 260 285. Patchornik A. 205. Peltzer E. T. tert. 170. Patel M. B. 15. Pendlebury R. E. 276. Paterson T. 556. Pennelle D. K. 362. Pathak M. A, 503. Penrose A. B. 221 374. Paton J. M. 150 255. Penswick J. R. 498. Paton R. M. 34 181. Penton H. R. 251. Patrick J. E. 139. Peover M. E. 24 239. Patrick M. H. 502. Pepin Y. 428. Pattabhiraman T. 15,43I. Pepperdine W. 464. Pattenden G. 527. Perciaccante V. 39. Patter D. E. 135. Pereira W.E. 40. Patterson D. 89. Perelman D. 450. Patterson D. B. 286. Pereyre M. 244. Perham R. N. 567 568. Patterson M. C. 504. Patton D. S. 115. Perie J. J. 255. Paudler W. W. 450 464. Perkampus H. H. 202. Paukstelis J. V. 266 Perkins M. J. 34 180,338 381. 341 342. Paul D. B. 182. Perlrnan R. L. 522. Paul D. P. 98. Perry W. O. 1 I. Paul H. 20 23. Person S. 493. Paul I. C. 47 51 62 309 Petcher T. J. 60. 449 501. Peterkofsky A. 558. Author Index Peters H. 525. Peters P. 370. Petersen R. C. 192 225 231. Peterson C. S. 61. Peterson D. J. 274. Peterson F. C. 212 213 214 505. Peterson G. 12. Peterson M. R. 252 366. Peterson P. 233. Peterson P. E. 132 148. Peterson R. F. 381. Peterson S. 447. Peterson U. 468.Petit M. 426. Petragnani N. 344. Petrissans J. 370. Petrovich J. P. 177 220 234. Petrow V. 424. Pettit G. R. 14 244 430 431. Pettit R. 280 306 308 325 376. Pews R. G. 437. Peynircioglu N. B. 275 344. Pfeffer P. E. 261. Pfeiffer F. R. 529. Pfleiderer G. 568 569. Phelps D. J. 384. Phelps J. 222. Philippides D. 449. Philipps G. R. 508. Phillipps G. H. 267 429. Phillips A. T. 565. Phillips B. E. 523. Phillips G. O. 14 216. Phillips G. T. 536. Phillips J. M. 213. Phillips R. F. 310. Phung N.-H. 317. Piacenti F. 322 323. Pichat L. 493. Pickard H. B. 136. Pickholtz Y. 314. Pidcock A, 312. Pierce H. D. 174 386. Piers E. 483. Pietra F. 100. Pigman W. 452. Pike J. E. 526 Pike P.E. 247. Pilbrow M. F. 314. Pillot J. P. 289. Pinder A. R. 407. Pines S. H. 12. Pinhey J. T. 421. Pinhey T. J. 425. Pinke P. A. 314. Pinkerton M. 62. Author Index Pinkus A. G. 277. Pinnick H. R. 130. Pinnick H. W. 114 266. Pino P. 323 324. Pinschmidt R. K. 169. 367 392. Pinson J. 283. Pinte F. 423. Piozzi F. 476. Pirkle W. H. 453. Pisciotti F. 289. Pis’man I. I. 316. Piszkiewicz D. 567. Pitha P. M. 507. Pitts J. N. 435. Placucci G. 21 31. Plapp B. V. 568. Plat M. 482. Platenburg D. H. J. M. 302. Platt A. E. 284. Plattner G. 32. Plattner J. J. 410. Plaut G. W. E. 556. PleSek J. 42. Pletcher D. 223 240. Pletcher J. 61. Pletcher T. C. 74 150. Pletcher W. A. 379.Pliml J. 449. Plimmer J. R. 205. Ploder W. H. 303. Plonka J. H. 170 172. Ploquin J. 260. Pober K. W. 526 527. Pocker Y. 107. Pojarlieff I. G. 72. Poland J. S. 272 300. Polgar N. 16 531 532. Poling M. 40 459. Pollack R. M. 67. Pollack Y. 517. Poller R. C. 271. Polston N. L. 285. Pomerantz M. 355. Pond D. M. 200 386. Pongs O. 491. Ponomarev S. V. 292. Ponsinet G. 417. Ponsold K. 254,434. Ponti P. P. 258. Poon L. 486. Pope W. J. 300. Pople J. 106. Pople J. A. 66. Popli S. P. -79. Popov A. I. 286. Poranski C. F. 65 135. Porri L. 320. Porschke D. 507. Porte A. L. 35. Porter R. D. 124. Portis L. C. 228. Posner G. H. 264 310. Post E. W. 283. Postic B. 490. Pot J. 424. Potier P.428 474 482 483. Potter D. E. 168. Potter S. E. 327. Poulos A. 530. Poulter C. D. 107 108 168. Poupko R. 30. Poutsma M. L. 177. Powell J. E. 376 455. Powell V. H. 249 41 1. Power D. M. 216. Powers D. R. 172. Powers J. W. 193. Poyser J. P. 430. Praat A. P. 323. Prange U. 101 328. Pratt A. C. 203. Pratt D. W. 18. Pratt R. F. 150. Preininger V. 472. Prelog V. 36. Prenton G. W. 473. Prescher G. 202. Preston K. 152. Pretty A. J. 327. Price M. J. 97 147. Price S. J. W. 305. Prichard P. M. 518. Prins R. 278. Prinzbach H. 170 349 434. Prislopski M. C. 263. Pritchard J. G. 440. Pritchett R. J. 31. Prokai B. 280 294. Prokop’ev B. V. 152. Prome J.-C. 524 529. Prosperini R. 299.Pross A. 248. Prostakov N. S. 450. Pruess D. L. 552. Priitz W. A. 217. Pryce R. J. 417. Pryor W. A. 187 188. Pschigoda L. M. 38. Ptashne M. 521. Puckett R. T. 363. Pudovik A. N. 273. Pura J. L. 262. Putkey E. 58. Puttner R. R. 79. Puuponen L. 279. Pyrek J. St. 358. Quass L. C. 290. Quast H. 435. Queen A. 152. Quin L. D. 302. Quinkert G. 202. Quinn H. A. 402. Quinn H. W. 306. Quintiliani M. 216. Quiocho F. A, 57. Quirk R. P. 63 64 102. Raaen V. F. 117. Raber D. J. 106 111 112 114 119 382. Rabideau P. W. 244 360 361 367. Rabin B. R. 496 570. Rabinovitz M. 349. Rabinowitz H. N. 30 309. Rabone K. L. 428. Raccla W. 64. Race G. M. 223. Rackham D. M. 366. Radda G. K. 568.Rademacher P. 433. Radlick P. 155. Radman M. 504. Radom L. 106. Radue R. 161 343. Rae W. J. 426. Raef J. 208. Raffauf R. F. 467. Ragoonanan D. 111. Rahimtula A. D. 57 1. Rahn R. O. 502. Raimonds R. F. 403. Raiser K. L. 318. Rajadhyaksha V. J. 174 386. Rajagopalan P. 459. Rajappa S. 444. RajBhandary U. L. 490 518. Rake A. T. 305. Rakita P. E. 165. Rakshys J. W. 102 180 327 328. Ramachandran V. N. 470. Ramage R. 398. Ramakrishnan V. 196. Ramasseul R. 21. Ramey C. E. 352. Ramsay G. C. 34. Ramstad E. 544. Ranade V. V. 430. Rhnby B. 28. Ranganathan S. 404. Ranganayarkava K. 124. 606 Author Index Rank D. M. 491. Renaud R. N. 11. Rimmelin P. 249. Ranzi B. M. 552. Renauld J.A. S. 417. Rinaudo J. 182. Rao D. R. 369. Renkes G. D. 195. Rindone B. 552. Rao G. S. 545. Renner C. A. 173. Rinehard R. E. 320. Rao S. T. 382. Rennison S. C. 310. Ringold H. J. 569 570 Raphael R. A. 288 374. Renold W. 407. 571. Rapoport H. 410 468. Renowden P. V. 83. Ripperger H. 55. Rapp M. W. 130. Rens M. 435. Ritscher J. S. 155. Rapp U. 9. Reske E. 262. Ritter G. 299. Rappe C. 140. Retey J. 535 559 560 Rittig F. R.. 283. Rappoport E. 149. 562. Rivett D. E. A. 418. Rappoport Z. 126 127 Rettig T. A. 19 177. Riviere H. 310. 128. Revel M. 517. Riviere P. 294. Rasmusson G. H. 429. Revet B. M. J. 521. Rizk D. 498. Ratajczak T. 540. Rey M. 388. Rizzo R. 62. Ratcliffe R. 247. Reynard K. A. 283. Roach L. C. 144 251. Rathke M. W. 261 274.Reynolds G. F. 429. Robbins W. K. 179. Rausch D. J. 197. Rhoades D. F. 502. Roberts B. P.,26 27 284. Rautenstrauch V. 167. Rhoads S. J. 369. Roberts J. D. 366 369 Rawston R. J. 375. Rhodes Y. E. 107. 370 497. Ray R. B. 13. Riad Y. 136. Roberts J. S. 35 57. Ray R. K. 515. Rice J. M. 497. Roberts J. W. 521. Razuvaev G. A. 279. Rich A. 517. Roberts M. 101 328. Read G. 334. Rich D. H. 252 528. Roberts P. A. 568. Rechler M. M. 518. Richard J. P. 305. Roberts P. J. 212. Reck G. 44. Richards C. N. 74. Roberts S. 388. Recsei P. A. 564. Richards D. H. 263 275. Robertson I. C. 321. Redfield D. A, 149. Richards E. M. 303. Robertson J. M. 46 48 Red’kina L. I. 317. Richards J. H. 495. 57 62 424. Redl G. 298 300. Richards J. T. 198 212. Robey R. L. 288 332.Ree B. R. 109. Richards K. E. 331. Robins M. J. 37 496. Reed R. G. 238. Richards P. J. 212. Robins R. K. 492 497. Reeke G. N. 57. Richards R. L. 308. Robinson B. 440. Rees C. W. 343. Richardson D. I. 82 496. Robinson C. 216. Rees D. A. 452. Richardson K. 443. Robinson. D. R.. 76. 152. Reese C. B. 168 254 314 Richardson W. H. 155. Robinson; J. B. 549. 377 381. Richey H. G. 115 116 Robinson J. C. 30. Regnick A. 97. 125. Robinson J. D. 571. Rehder-Stirnwess W. 3 14. Richie C. D. 129. Robinson K. K. 322 Rehman Z. 127. Richman J. E. 246. Robinson L. 63 83 00. Rei M. H. 150. Richter P. 501. Robinson R. 65 66. Reich H. J. 366 370 Richter W. 403. Robinson R. J. 12. 381. Rickborn B. 264,384,437. Robinson S. D. 313. Reich I. L. 376 381. Ridd J. H. 90.Robinson W. G. 561 Reichardt P. B. 536. Riddell W. D. 202. Robson B. 568. Reichenthal J. 460. Riddle C. 273. Rocchio J. J. 383. Reich-Rohrwig P. 39. Rieber N. 174. Rocek J. 247. Reid B. R. 493. Riechmann M. E. 492. Rochow E. G. 272. Reid C. G. 182. Riehl J. J. 256. Rockett B. W. 130. Reid K. I. G. 309 449. Rieke D. 31. Rockley M. G. 195. Reikhsfel’d V. O. 312 Riemann J. M. 392. Rodehorst. R.. 247. 319. Rieper W. 364. Rodgers M. A. J. 211 Reimlinger H. 169 255 Rietveld H. M. 46. 212. 260 306 446. Rieva-Figueras J. 101 Rodighiero G. 503. Reinders F. J. 278. 338. Rodin J. O. 525. Reinecke M. G. 460. Rigaudy J. 204. Rodrigo R. 473. Reinehr D. 278 286. Riggs A. D. 521. Rodriguez-Siurana A. Reinheirner H. 318. Riley F. 507. 101 338. Reisdorf J.353. Riley P. N. K. 282. Roe D. K. 33 245. Reisse J. 370. Riley W. D. 564 565. Roe D. M. 344. Reist E. J. 530. Riman J. 51 5. Roe R.,Jun. 157 388. Rempel G. L. 241 310. Rimerman R. A. 369. Roebke H. 259. Author Index Rohle G. 453. Rohrl M. 417. Roehrl M. 60. Ronnquist O. 59. Rottele H. 354 372. Rogers D. 15. Rogerson P. F. 9. Rogido R. 157. Rogne O. 88. Rokutanda H. 515. Rokutanda M. 515. Rolfe R. E. 25. Rolle F. R. 90. Roller P. 422. Roman V. K. 272. Romo J. 407. Rooney J. J. 402. Root K. D. J. 20 189. Rosati R. L. 483. Rose F. L. 458. Rose I. A. 572. Rose J. G. 260. Rosen M. 439. Rosenblum M. 399. Rosenfeld J. 125. Rosenfeld J. M. 426. Rosenstein R. D. 60 62. Rosenthal D.9. Rosenthal I. 202 503. Rosenthal J. W. 329. Rosito C. 419. Ross C. A. 496. Ross C. D. 192. Ross F. K. 60. Ross F. P. 536. Ross J. F. 286. Ross S. D. 225 23 1. Rosser M. J. 149. Rossi R. 367. Rossi R. A. 341. Rossmann M. G. 57,497 567. Rostock K. 304. Rotenberg D. H. 449. Roth H. 391. Roth J. F. 322. Roth J. R. 518. Roth W. R. 165 393. Rothbaum P. 239. Rothberg I. 121. Rothweiler N. 15. Rottman F. 505. Rouk A. 136. Rouessac F. 257,336,375. Rouschias G. 308. Rousseau Y. 8. Rowland N. E. 444. Roy J. 309. Roy S. K. 179. Royer R. 259. Rozanis J. 524. Rozantsev E. G. 177. Ruasse M.-F. 148. Rubin M. B. 398. Rubinstein M. 30. Rudashevskaya T. Yu. 384. Ruddick J. D. 310.Ruden R. A. 41 1. Rudkovskij D. M. 323. Rudolph R. W. 296. Rudolph S. E. 278. Ruchardt C. 180,340,341. Rudiger W. 440. Rueppel M. L. 468. Ruff J. K. 22. Ruiz V. M. 334. Ruliffson W. S. 16. Rumin R. 167. Rumpf P. 279. Rupp R. 39. Ruprecht H. D. 232 234. Rusasse M. F. 97. Rushworth A. 130. Russell G. A. 22 31 32 33. Russell K. E. 35. Russell R. 51 1. Russell R. L. 508. Rutledge P. S. 421. Rutledge T. F. 156 319. Rutter A. W. 25. Ryan G. 344. Ryan K. J. 495. Ryan T. J. 157. Ryang M. 324. Ryback G. 561. Rylander P. N. 272. Ryles A. P. 554. Rymo L. 51 1. Sabine T. M. 53. Sabol M. A. 236. Sabol S. 517. Sachdev H. S. 268. Sachdev K. 199. Sachdev P. 155. Sadler I. H. 357. Saenger W.58,495. Saethre L. J. 449. Sauberli U. 412. Safe S. 11. Saffhill R. 491. Sahini V. E. 35. Sair M. I. 420. Saito I. 204. Saito K. 529. Saito S. 406 494. Saito T. 434. Saito Y. 45 48 494. Sajgo M. 567. Sakai M. 119. Sakai S. 288. Sakan F. 41 1. Sakan K. 162. Sakata Y. 350 355. Sakore T. D. 59. Saksena A. K. 430. Sakurai H. 189 293 294. Sakurai T. 48. Salamon G. 347. Salamone R. A. 157. Salaun J. 384. Salem L. 168. Sales K. D. 18 25. Salib K. A. R. 282. Salisbury K. 356. Sallam L. 425. San Filippo J. 280 310. Salo W. L. 573. Salomon M. F. 324. Salomone R. A. 14. Saltikova I. A. 417. Salvadori P. 324. Salvesen K. 75. Samek Z. 412,494. Sammes P. G. 247 403 430.Sample Woodgate S. D. 12. Samuel D. 68. Samuel G. 45. Samuelsson B. 237 531. Samuelsson K. 531. Samuni A. 28. Sandaralingam M. 453. Sanders G. M. 424. Sanders If. 524. Sanders J. R. 279. Sandstrom J. 97. Sanford A. 312 429. Sanford E. C. 203. Sanger F. 490 508. Sangster D. F. 208. Sano T. 423. Santavy F. 39,472. Santelli M. 392. Santhanakrishnan T. S. 408 417. Santhanam K. S. V. 31 239. Santhanam M. 196. Santi D. V. 493. Santry D. P. 38. Sarel S. 267 333 430. Sarfati R. 481. Sargent G. D. 107 125. Sargeson A. M. 79. Sarma R. H. 496,497. Sarma R. S. 566 567. Sasada Y. 47 485. Sasaki T. 205 348 460. Sass R. L. 46 60 61. Sasse J. M. 418. Satchell D. P. N. 72 75 83. 608 Author Index Satge J.294. Sato A. 418. Sato H. 40. Sato T. 62. Satsumabayashi S. 257. Sattar A. 398. Saucy G. 41 1. Sauer J. 380. Sauer K. 42. Sauer M. C. jun. 211. Sauerbier J. 15. Sauermann G. 276. Sauers C. K. 77. Sauers R. R. 40 120. Saunders J. K. 328 473. Saunders M. 125. Saunders W. H. 143 252. Sauvage J. P. 465. Savona G. 476. Sawada S. 167. Sawai H. 314. Sawyer D. T. 239. Sax M. 61. Sbrana G. 323. Scanlon B. 249. Scelly N. F. 275. Schaaf A. P. 440. Schaaf T. K. 525. Schaal R. 100. Schaap A. P. 155 204. Schachter E. M. 512. Schafer H. 222 223. Schaefer H. F. tert. 172 Schafer W. 156. Schaeffer D. J. 275. Schaeffer R. 271. Schafer T. W. 508. Schaffner K.424. Schaffrin R. 62. Schairer H. U. 417. Schaleger L. L. 74. Schallhorn C. H. 158,316 400. Schamberg E. 209. Schaper K. J. 283. Scharf D. J. 374. Scharf G. 267. Scharf H.-D. 378. Schaumburg K. 532. Schechter H. 248. Scheer H. 292. Scheffer J. R. 155 247. Scheffler K. 35. Scheidegger U. 482. Schell R. A. 323. Schellenberg K. A. 569 572. Scherer 0.J. 300. Scheuer P. J. 431. Scheuer P.L. 15. Schevitz R. W. 497 567. Schissel P. 173. Schlatmann J. L. M. A, 114. Schleif R. F. 522. Schlenk H. 523. Schlesinger G. 320 402. Schlessinger D. 518. Schlessinger R. H. 444 461. Schleyer P. von R. 105 106 110 111 112 114 119 120 121 126 365 382. Schlimme E. 510. Schlogl K. 39. Schlom J.515. Schlosberg R. H. 102. Schlossel R. H. 25. Schlosser M. 172 258. Schmalzl K. J. 41 1. Schmid G. 272. Schmid H. 8 15 40 166 167 204 335 487. Schmid H. G. 204. Schmidbaur H. 272 296 306 310. Schmidt D. A. 522. Schmidt E. K. G. 376. Schmidt G. M. J. 46. Schmidt M. 283 301. Schmidt R. R. 159 266. Schmir M. 521. Schmitt E. 435. Schmitz F. J. 15 431. Schnabel W. 209. Schneck G. E. 398. Schneider H. 531. Schneider W. 266 454. Schneider Z. 560. Schnepp O. 42. Schobel Gy. 96. Schoeller W. 164. Schollkopf U. 167 168 174 179 272 274 327. Schoenfelder M. 249. Schofield K. 78 90. Scholes G. 213 214 215 505. Scholfield C. R. 533. Scholz H. 304. Schorno K. S. 468. Schossig J. 179.Schram H. 339. Schrauzer G. N. 30 309 320 402. Schreiber K. 55 424. Schreiber W. L. 471. Schreibman A. A. P. 245. Schrock R. R. 241 310. Schroder G. 101. Schroeck C. W. 375. Schroder B. 166. Schroder F. W. 292. Schroder G. 160,280,328. 354 367 372 387. Schroder K. L. 236. Schroeder L. R. 69 151. Schroeder S. R. 147. Schroepfer G. J.,jun. 528. Schroll G. 17. Schubert H. 305. Schubert W. M. 113. Schue F. 249. Schuett W. R. 31 1. Schiitz G. 450. Schulman J. M. 372. Schulz G. 425. Schuster D. I. 201 202. Schutzbach J. S. 574. Schwab W. 307. Schwager I. 95. Schwartz A. W. 491. Schwartz D. 522. Schwartz J. 168. Schwartz J. A. 154 395. Schwartz R. N. 178. Schwarz G. 506. Schwarz M.A. 477. Schwarz W. 85 302. Schweickhardt C. 358. Schweizer E. E. 303. Schweizer M. P. 494 506. Schwert G. W. 568. Schworer F. 210. Sciacovelli O. 366. Scilly N. F. 263. Scolastico C. 552. Scopes P. M. 39 41. Scott A. I. 38 367 483 536. Scott F. L. 132 448. Scott R. M. 64 179. Scriven E. F. V. 174 337. Scriver R. L. 131. Scrosati B. 240. Scrowston R. M. 90 444. Sebesta K. 494. Secemski I. I. 72 75. Seddon D. 222,249. Seddon W. A. 212. Sedlar J. 200. Sedmera P. 40 472. Seeback D. 35. Seelkopf C. 486. Seeman J. I. 201. Segnini D. 418. Seibl J. 559. Seichter F. S. 404. Seidel H. 510. Seidl P. 109. Seidner R. T. 159 242 381. Seiler M. 536. Seitz G. 445. Sekerra A. 279. Author Index Sekert M.D. 117. Seki H. 494. Sekiguchi M. 504. Sekiguchi S. 67. Sekita T. 56. Selema M. D. 421. Seligmann O. 62. Senatore L. 89 131. Senda Y. 242 384. Sen Gupta A. K. 525. Senior J. B. 282. Sepulveda L. 83. Sereltas C. G. 275. Serratosa F. 348. Serum J. W. 7. Serve D. 227. Servis K. L. 153,266,315. Servis R. E. 493. Setaka M. 28. Sethi M. L. 471. Setkina V. N. 114. Setlow R. B. 504. Seto H. 453 549. Seto M. 550. Seto S. 31. Sevilla M. D. 31. Seyferth D. 172 280 281 290 294 297 325 375. Sgaramella V. 490. Sgoutas D. S. 524. Shaffer G. W. 408. Shafiei A, 250. Shaford R. J. 31 1. Shafritz D. A. 518. Shalon Y. 430. Shandrinov N. Ya. 301. Shank N. E. 212. Shanks R.A.73. Shanshal M. 174. Shapiro J. 490. Shapiro M. B. 500. Shapiro R. 493. Shapiro R. H. 7. Shapiro S. A. 64. Sharman E. 42. Sharp J. A. 20. Sharp J. H. 20. Sharp J. T. 341. Sharpe L. 376. Sharpe L. A. 381. Sharpe M. 328 371. Sharpless K. B. 423. Shary-Tehrany S. 365. Shaw A. 168 254 314 377. Shaw B. L. 308 313. Shaw C. F. 272. Shaw G. 452. Shaw J. E. 407. Shaw M. A. 304. Shaw M. J. 30 267. Shaw N. 558. Shaw P. 215. Shun-Ichi Murahashi 226. Shaw P. M. 425. Shusarczuk G. M. J. 448. Shaw S. J. 497. Shutt J. R. 301. Shchepinov S. A, 293. Sicher J. 369. Shealy Y. F. 495. Sickier B. R. 120. Shechter H. 65 136 188. Sicsic S. 450. Shefter E. 60 506. Siddall J. B. 528. Sheinker Yu. N. 330.Siddiqui A. H. 246. Sheldon R. A. 27 184 Sidwell W. T. L. 455. 185. Siebert W. 283. Sheldrick G. M. 289. Siegel A. S. 12. Sheldrick W. S. 289. Sierra J. 63. Shelton G. 441 442. Sigal P. 196. Shelton K. W. 443. Sigel C. W. 417. Shemyakin M. M. 180. Sigg H. P. 40. Shen T. Y. 495. Sigwalt C. 205. Sheng M. N. 247. Silbert L. S. 261. Shenhav H. 149. Sillero M. A. S. 517. Shepherd R. A. 343 401. Silver B. L. 30. Sheppard R. C. 492. Silver M. J. 530. Sheppard W. A. 96. Silverstein R. M. 525. Sheradsky T. 440. Sim G. A, 53 54 56 287 Sherman W. R. 12 13. 308 474 487. Sherrod S. A, 121. Simamura O. 181 185 Shevlin P. B. 172 381. 244 266 340. Shibata S.. 55. Simanek V. 472. Shibuya K. 493. Simchen G. 449 458. Shiekh V. M. 17. Simchen P.543. Shiga T. 28. Sime J. G. 48 52 321. Shih S. 29. Simeone J. F. 245. Shimadzu H. 457. Simes J. J. H. 419. Shimakawa Y. 157. Simic M. 215. Shimamoto N. 20. Simon H. 31 1 452. Shimanouchi H. 47 485. Simonet J. 238. Shimizu Y. 28 58 429. Simonetta M . 44 100 126. Shin H. 41 1. Simonsen O. 205. Shine H. J. 32. Simonsen S. H. 44. Shiner V. J. 11 I 130. Simonson L. A. 229. Shinga H. 67. Simpson A. F. 23. Shingu T. 406. Simpson C. C. 92. Shinkai S. 71. Simpson P. G. 55 480. Shione R. 62. Simpson W. K.J. 347. Shiori T. 254. Simundza G. 59. Shirahama H. 411. Sineokov A. P. 434. Shire D. J. 498. Singh B. B. 404. Shiro M. 62. Singh N. 54. Shirrida K. 504. Singh P. 61. Shishido K. 472. Sioumis A. A. 475 478 Shoemaker M. J. 179.486. Shono T. 190 231 345. Sisido K. 300. Shoppee C. W. 421. Sjoberg B. 439. Shorter J. 73. Sjoquist J. 57. Shortland A. 273 310. Skaletz D. H. 235. Shotani A. 310. Skell P. S. 170 172. Shotton D. M. 57. Sketchley J. M. 343. Shriver D. F. 241 279 Skidanow H. 121. 311. Skinner S. J. M. 571. Shroeck C. W. 266. Skold C. N. 444. Shugar D. 505. Skoyles D. 358. Shulman J. I. 164 257 Skramstad J. 356. 258 304. Slack W. E. 439. Shulman R. G. 504. Slade R. M. 313. 610 Author Index Slae S. 95 141. Snatzke G. 37 39 40 41 Srinivasan M. 472. Slama F. J. 132. 417 428 472. Srinivasan R. 199. Slater J. 33. Sneath T. C. 60. Srivastava R. C. 298. Slates H. L. 526. Snell E. E. 564 565. Staab H. A. 9 350. Slatten J. 5 1. Snider T.E. 297. Stacey G. J. 458. Slaugh L. H. 319. Snieckus V. 174 205. Stackhouse J. F. 337. Slavik J. 40 472. Snipes W. 505. Stadtman E. R. 560. Sledge M. J. 428. Snow G. A. 523. Stadtman T. C. 558 562. Sletten E. 59. Snow J. T. 244 285. Stallberg-Stenhagen S. Sletten J. 449. Snyckers F. 91 92. 532. Sliwa H. 450. Snyder E. 149. Staiey S. W. 383. Sliwinski W. F. 121. Snyder E. I. 160. Stam M. 83. Slotboom A. J. 530. Snyder L. C. 368. Stam M. F. 205. Slough L. H. 323. Snyder L. E. 491. Stammer R.,34. Slusarchyk W. A. 419. Sobell H. M. 58 59. Stanbury P. F. 157. Sluski R. J. 375. Sobti R. R. 408. Stanek J. 452. Smais M. F. 313. Soderberg E. 57. Stang P. G. 126. Smallcombe S. 191 373. Smensen N. A. 423. Stang P. J. 119. Smalley R. K. 174. Soffer M. D.412. Stanko J. A. 52. Smentowski F. J. 24. Solomon D. M. 526 527. Stanoraya S. S. 281. Smid R. 274. Solveson K. 133. Stapleford K. S. J. 484 Smiley I. E. 567. Soma N. 329. 543. Smith,A. B. tert. 161 195. Sommer J. M. 249. Staples M. 514. Smith A. E. 518. Sommer L. H. 264. Staples T. L. 25. Smith C. A. 287. Sondheimer F. 134 310 Starer I. 94 330. Smith C. R.,jun. 523,532. 349 355 444 464 465. Stasiewicz M. 73 113. Smith D. J. H. 301. Soneda R. 257. Stasiuk L. 494. Smith D. L. 50. Sonoda N. 247. Staudinger G. K. 160. Smith E. H. 162,251 547. Sorensen A. K. 453. Stears N. D. 90. Smith E. L. 558 567. Sorensen T. S. 124. Steckhan E. 223. Smith E. M. 255,261,459. Sbrm F. 407,494. Stedronsky E. R. 310. Smith F. H. 538. Soto J. L. 447. Steer R. J. 46.Smith G. F. 483 484 Sotoh D. 16. StefanoviC M. 413. 543. Sousson G. 279. Stegel F. 99. Smith G. M. 30. Southaam R. M. 200. Stegmann H. B. 35. Smith G. N. 483 543. Southern E. M. 520. Stehouwer D. M. 155 Smith G. R. 529. Spahr P. F. 490. 345 375. Smith G. V. 31 1. Spalding T. R. 282. Steigel A. 380. Smith. I. C. P. 496. Spanier E. J. 301. Steigman J. 63. Smith J. D. 287 508 Sparks R. A. 506. Stein K. 165. 511. Speakman J. C. 52. Stein M. T. 52. Smith J. G. 145. Speckamp W. N. 445,450. Stein R. A. 525. Smith J. H. 75 152. Speidel T. 314. Steiner R. 506. Smith J. S. 10. Speier G. 314. Steinfeld A. S. 227 439. Smith K. 187 188 256 Speier J. L. 294. Steinhauser S. 287. 285. Speight J. G. 182 341. Steinman G. 491. Smith K. C. 503. Spence G. G.205. Steinmaus H. 503. Smith L. 157. Spence M. J. 88. Steinrauf L. K. 62. Smith L. W. 467 468. Spenser I. D. 545 546 Steitz J. A. 490. Smith M. 498. 547. Steitz T. A. 57. Smith M. B. 286. Spiegelman S. 5 15. Steller K. E. 199. Smith M. J. 443. Spitzer W. A. 201. Stelmach H. 72. Smith N. A. 18 20. Spitzner E. B. 482. Stempel A. 552. Smith P. 29 46. Sporfel L. 260. Stenhagen E. 527. Smith P. J. 143 273. Spratt R.,310. Stent G. S. 518. Smith R. C. 149. Sprecher M. 562. Stepanov B. I. 300. Smith R. M. 423 485. Sprinson D. B. 562. Stepanov F. N. 387. Smith S. G. 141 278. Spritzer M. S. 240. Stephan E. A,,464. Smith T. A. 495 565. Sprogl J. 230. Stephens D. N. 60. Smolka H. G. 282. Sprouse C. T. jun. 158. Stephenson L. 267 429. Smolyakov V. S. 180.Spry D. O. 438. Stepina E. M. 287. Smythe G. A. 441 442. Spurlock L. A. 117. Sterba V. 77 91. Author Index Sterlin R. N. 272. Sterlin S. R. 137 281. Sternhell S. 90 248. Stetter H. 262. Stevens G. 172. Stevens G. C. 213. Stevens I. D. R. 141. Stevens J. G. 305. Stevens R. D. 29. Stevens R. V. 442. Stevenson G. R. 24 3 1. Stevenson R. 427. Stewart A. P. 300. Stewart J. A. G. 357. Stewart J. C. 540. Stewart J. M. 50 61. Stewart 0.J. 96. Stewart R. 135. Sticher O. 406. Stigliani W. M. 368. Still I. W. G. 9 404. Stille J. K. 324. Stinson R. A, 568. Stirling C. J. M. 141. St. Jacques J. 369. Stochilski L. P. 279. Stock L. M. 23. Stockhausen K. 209. Stoddart J. L. 540. Stocker F.35. Stocklin W. 40 413. Stoffer J. O. 11 1. Stogryn E. L. 185. Stojiljkovic A. 190. Stoll M. 412. Stollar H. 428. Stolzenbach F. E. 568. Stone F. G. A. 313 318 321. Stone T. J. 3 1. Stoodley R. J. 439. Storey P. M. 29 139 188. Storey R. A. 21 177. Storm C. B. 441. Storm D. R. 557. Storm P. C. 132 133. Story P. R. 378. Stothers J. B. 360 367. Stout G. H. 40 459. Stowell J.C. 164,187,316 362 397 399. St. Pyrek J. 416. Strachan W. M. J. 79. Strafford R. G. 287. Strauss M. J. 97 339. Strausz 0.P. 157. 173. Strehlow W. 444. Streith J. 205. Streitwieser A. 90,95 113. Strickberger M. W. 492. Strickland R. C. 110. Strobach D. R. 498. Strohmeier W. 31 1 314. Strom E. T. 22 23 33. Strominger J.E. 574. Struble D. L.. 190. Struchkov Yu. T. 306. Stuart K. L. 543. Stubbs M. 166. Stuchal F. W. 114 266. Stucky G. D. 286 287. Studer R. O. 14. Sturm W. 353 354. Sturtevant R. L. 20. Sturtz G. 304. Stusche D. 170 434. Su S. R. 321. Suard M. 19. Suares H. 486. Suarez Z. 569. Subba Rao G. 376 471 472. Subba Rao G. S. 41 1. Subba Roa G. S. R. 244. Subramaniam P. S. 470. Subramanian E. 59. Suchf M. 407. Suciu N. 66 446. Suck D. 58. Sucrow W. 242,403. Suelter C. H. 572. Suffness M. I. 472 474. Suga T. 404. Sugasawa S. 260. Sugavanam B. 471. Sugimura Y.,329. Sugita M. 476. Sugiura M. 522. Suhr H. 359. Suissman E. E. 144. Sukawa H. 202. Sukh Dev. 408. Sukhoverkhov V. D.387. Sukkestad D. R. 531. Sukornik B. 20. Sullivan A. B. 268. Sullivan P. D. 18 26 30. Sulzbach R. A. 290. Sumiki Y. 414. Summers W. C. 521. Summerville R. H. 126. Sunarnoto J. 83. Sund H. 566. Sundaralingam M. 51,58 368 373 382 506. Sundberg R. J. 174. Sunde E. 423. Surzur J. M. 34. Suschitzky H. 174. Sussman D. H. 202. Sussmuth R. 493. Susuki T. 323. Sutcliffe B. T. 19. Sutcliffe L. H. 34. 611 Suter S. R. 174. Sutherland G. L. 17. Sutherland H. H. 46. Sutherland I. O. 167 327 328 332. Sutherland J. K. 168,254 377 379. Sutherland R. G. 337. Suzuki A. 14 284. Suzuki H. 521. Suzuki M. 412. Suzuki O. 533. Suzuki R. 170. Suzuki S. 493. Suzuki T. 415 517. Svejda P. 19. Swallow A.J. 208 210 215 217. Swan 1. D. A. 57. Swann B. P. 250 332. Swanwick M. G. 33 35 338. Swartz S. L. 363. Sweeney A. 441. Sweeny J. G. 536. Sweet S. A. 124. Swenton J. S. 203. Swift D. 487. Swift H. E. 320. Swiger R. T. 114 266. Swindell R. T. 110. Swingle R. B. 440. Switzer R. L. 562. Sykes A. 212. Symons M. C. R. 20 24 26 33 35. Syrov A. A. 177. Szabo A. G. 202. Szeimies G. 168. Szelke M. 530. Szell T. 96. Szilagyi S. 186. Szilagyi I. 14. Szmant H. H. 171. Szwarc M. 25. Tabata T. 166. Tabner B. J. 31. Tabor C. W. 565. Tabor H. 565. Tabushi I. 172 382 439. Tada H. 289. Taddei F. 31 182 310. Taga T. 54 56 57 487. Tagaki W. 87. Taguchi T. 268. Tai Y.-H. 372. Takagi S.62. Takagi Y.,453 504. Takahashi A. 320. Takahashi H. 12 322. Takahashi K. 139 349. Takahashi N. 14 172 382. Takahashi S. 243. Takaku M. 444. Takakura K. 28. Takamura N. 494. Takanami M. 522. Takanohashi K. 491. Takase K. 343 349. Takatsuki K. 163 391. Takaya H. 401. Takaya T. 180. Takeda K. 407,409. Takeda T.,485. Takeda Y. 406. Takemoto T. 16,430. Takemura S. 508. Takenishi T. 491. Takesada M. 322. Takeuchi Y. 31 1. Takino T. 107. Takizawa T. 345. Talaty E. R. 435. Talwar S. S. 341. Tam J. N. S. 171. Tamagaki S. 96. Tambute A, 167. Tamm Ch. 15 455. Tamura C. 54,487. Tamura F. 319. Tamura S. 14. Tamura Y. 439. Tan C. C. 180 340 341. Tan J. C. 129. Tan S.L. 451. Tanabe M. 549 550. Tanaka H. 474. Tanaka K. 474. Tanaka M. 289,493. Tanaka R. 333. Tanaka T. 273,486. Tanemura M. 415. Tang R.,302. Tani H. 287. Tani S. 474. Tanida H. 119. Tanigaki T. 282. Taniguchi H. 29. Tanner D. D. 178. Tao T. 253. Tarbell D. S. 67 152. Tardivel R.,229. Tarhan H. O. 90. Tarhan S. 90. Tashiro M. 96. Tate K. R. 67. Taticchi A. 96. Tatlow J. C. 182,227,267. Taub D. 526. Tavale S. S. 58. Tavares D. F. 303. Tavs P. 301. Tayim H. A. 325. Taylor D. A. 484 543. Taylor D. A. H. 419,422 423 424. Taylor D. R. 423. Taylor D. W. 95. Taylor E. A. 25 1. Taylor E. C. 180,205,250 265 268 272 288 332 374 529. Taylor E. K. 509. Taylor G. R. 97. Taylor I.C. 131 325. Taylor J. W. 130. Taylor K. A. 306. Taylor K. G. 383. Taylor P. J. 50 458. Taylor P. R. 494. Taylor R. P. 98 339. Taylor R. T. 564. Taylor S. H. 310. Tchernatinsky C. 426. Tebby J. C. 303 304. Teitel S. 477. Tel L. M. 136. Teller G. 12. Temin H. M. 489 515. Temnikova T. I. 436. Temple D. L. 261 459. Teoule R. 505. Teranishi S. 3 17,325,333. Ternay A. L. 360 367. Terrier F. 100. Tesaret J. M. 9. Teuber H. J. 450. Tevdoradzi E. A. 28 1. Tewari P. H. 21 1. Tezuka M. 359. Thach R. E. 517. Thal C. 483. Thaler W. A, 177. Thaller V. 409. Theard L. M. 212 213 2 14 505. Thebtaranonth Y. 167 327. Thewalt U. 58 301. Thibault J. 512. Thiele K. H. 284. Thielmann H.W. 417. Thiessen W. E. 55. Thomas A. 18 177,45 1. Thomas A. F. 403 404 410. Thomas C. A. 518 520. Thomas C. B. 8 96 192. Thomas C. W. 80. Thomas D. W. 14 524. Thomas. H. T.. 38. Thomas J. K. 198,208,2 12. Author Index Thomas M. B. 455. Thomas M. D. 88. Thomas M. T. 9. Thomsen A. D. 236. Thompson A. R. 96. Thompson D. T. 306. Thompson H. W. 159 331 390 Thompson J. L. 526. Thompson T. W. 458. Thomson A. 67. Thomson C. 18,19,31,34 35 175 181. Thomson J. A. 16. Thomson R. H. 188 357. Thorburn S. 96. Thoren S. 37. Thornton D. D. 491. Thornton D. E. 173. Thornton I. M. S. 422. Threlfall D. R. 555. Thummel R. P. 264 437. Tichy M. 369. Tickle P. 63 172. Tiecco M. 181 182. Tieckelman H.168. Tietze L.-F. 455. Tighe B. J. 88. Tikhomirov B. I. 31 1. Tillett J. G. 8 72 79 87. Timmons C. J. 199. Tindall C. G. jun. 174. Ting R. C. 516. Tinkler R. B. 448. Tinyakova E. I. 317. Tippett W. 196. Tjarks L. W. 523 532. Tobias R. S. 289. Tobita S. 406. Tocanne G. 524. Tocanne J.-F.,524 532. Toda F. 436. Toda T. 231 345. Todd K. H. 314. Todd L. J. 272. Todd P. F. 177. Toft P. 428. Tokoroyama T. 406. Tokumaru K. 178. Tukunaga F. 504. Tokura N. 7. Tollin P. 58. Tolstikova N. G. 293. Tomaszewski J. E. 264. Tomie M. 494. Tomiie Y. 62. Tomilov A. P. 301. Tomita B. 412. Tomkins G. M. 571. Tompkins D. C. 154 394. Tonellato U. 143. Toniolo C. 39. Author Index Toome V.41. Topp A. 359. Topping R. M. 69. Topsom R. D. 90 330. Tordo P. 22 34. Tori K. 407 409. Torkelson A. 528. Torre G. 36 42. Torssell K. 25 34 189. Toscano V. G. 344. Tournier H. 357. Tove. S. B. 538. Townes C. H. 491. Towns R. L. R. 52. Tozyo I. 407. Traaetleberg M.,371. Trapp C. 22. Travers A. A. 521 522. Travis K. 465. TravniEek M.,515. Traxler P. 15. Traylor T. G. 107 125 300. Traynham J. G. 220. Trecker D. J. 154 247 388. Trefonas L. M.,45 52. Treichel P. M.,322. Trent J. E. 124. Trifunac A. 32. Trifunac A. D. 23 179. Trimm D. L. 242. Trinajstic N. 461. Trindle C. 153. Trippett S. 85 87 300 301 302. Trivedi B. C. 86. Trofinov B. A. 152. Troll T. 380. Trosko J.E. 502 505. Trost B. M. 266 355 375 376 390 407 523. Trotter J. 57 61 62. Trozzdo A. M. 161 178. TrSka P. 41 428. Trudell J. R. 12. Trueblood K. N. 48 506. Truelock M. M. 273 310. Trujillo J. 467. Truscott T. G. 212. Truter M. R. 289. Tsai J. H. 306 320 402. Tsai L. 562. Tsai T. Y. R. 486. Tselinskii I. V. 135. Tsizin Yu. S. 523. Ts'o P. 0. P.. 491 506 507. Tsubodi M. 58. Tsuboyama K. 497. Tsuchihashi G. 12 336. Tsuchiya. T. 453. Tsuda K. 79. Tsuda Y. 423 562. Tsuji J. 306 322 323. Tsukuda Y. 62. Tsung-tee Li 528. Tsuruta H. 204. Tsushima T. 119. Tsutumi S. 247 324. Tsyskovskii U. K. 177. Tubul A. 525. Tuccarbasu S. 190. Tuck B. 350. Tucker A. N. 531. Tudor R. 26 284. Tunemann W.353. Tufariello J. J. 255 285. Tukhar A. A. 304. Tullbane R. J. 305. Tulley A. 267 429. Tullrnan G. M. 190. Tumbull K. W. 537. Tundo A. 181 182. Turchin K. F. 330. Turk J. 7. Turnblom E. W. 171 303. Turnbull K. W. 406. Turner A. 71 558. Turner A. B. 334. Turner D. L. 530. Turner W. V. 453. Turro N. J. 140 155 195 200. Tursch B. 15 431. Tweedale A. 282. Tweeddale H. J. 468. Tyler J. K. 370. Tyler V. E. 544. Tyssee D. A. 80 85 234 302. Tytell A. A. 507. Ubasawa M. 498. Ubersax R. W. 122. Ucciani E. 525 528. Uchida Y. 310. Uchino M. 317. Ueda S. 406. Uff B. C. 451. Ugo R. 306. Uguagliati P. 324. Ukita J. 510. Ullrich J. 441. Ulrich L. 204. Uma V. 175. Umani-Ronchi A.559. Umeno M. 294 312. Umezawa S. 453. Underwood G. R. 20 21 23. Underwood J. G. 77. Ungar F. 569. Unran A. M. 323. Uraseki I. 94. Urban F. J. 139 167. Usher D. A. 82 496. Ushio M. 33. Uskokovic M. 41 470. Uskokovic M. R. 472. Usubillaga A. 486. Utermoehlen C. M. 435. Utley J. H. P.,25,235,236. Utsumi Y. 62. Uyeo S. 54 476 487. Vacheron M. J. 531. Vaciago A. 49. Vagelos P. R.. 532. Vaishnav 1'. Y. 545. Valade J. 2Y6. Valenta Z. 384 469. Valentova M. 230. Vallarino L. M. 324. Valle G. 50. Vallee B. L. 570. Valls J. 348. Van Bever W. 427 430. van Deenen L. L. M. 530. van de Haar F. 510. Van den Hoek W. J. 25. van der Ent A. 309 310. Van der Hart W. J. 21. van der Hoeven M.G. 438. van der Kerk G. J. M.,297 306. van der Lugt W. T. A. M. 157 315 400. van der Plas H. C. 457 458. Van der Put P. J. J. M.,35. van de Sande J. H. 490 van de Ven L. J. M. 165 167 398. Vandewalle J. J. M. 446. Van Doorn J. A. 94 102 103. van-Driel H. 198. Van Drunen J. A. 134 135. van Eys J. 566. van Gaal H. 310. Vangedal S. 14. Van Gemert M. J. C. 25. Van Helden R. 325. Van Henegoniven G. M. 100. Van Horn M. F. 268. Van Lear G. E. 15 459 494. van Leusen A. M.,260. VanPeppen,J. F.,241,311 314. van Remoortere F. P. 45. Van Rietschoten J. 299. Van Soest T. C. 309. Van Tamelen E. E. 168 169 264 41 1 481 528 541. Vantillard A. 528. Van-Vliet A. 198. van Vuuren P.J. 359. Van-Wageningen A. 201. Varghese A. J. 502 503. Varma K. R. 541. Vasilianskas A. 343. Vaughan J. 33 1. Vaughan W. R. 279,404. Vaziri C. 369. Vazzoler A. 99. v. Deursen F. W. 460. v. d. Heeden M. E. 460. Veazey R. L. 110. Vecera A. 65. Vecera M. 77 91. Vedejs E. 164 324 343 362 397 401. Veefkind A. H. 263. Veidis M. V. 62. Veith H. J. 487. Velick S. F. 567. Velkon M. R. 110. Velluz L. 36. Venanzi L. M. 324. Venema A. 11. Venkataraghaven R. 17. Venkataraman B. 3 1. Venkstern T. 508. Vereshchenskii I. V. 177. Verghese J. 403. Verma A. K. 41 1. Vermes J. P. 255. Vernin G. 182. Vestling M. M. 142. Via F. I. 77. Vialle J. 448. Vicenzi C. 21. Victor R. 267 333. Vida J.A. 267. Viehe H. G. 136,260,451. Vietmeyer N. D. 39. Vig 0.P. 410 41 1. Vijayanagar H. M. 478. Vilim A. 486. Vilkas E. 531. Vilsmaier E. 304. Vincow G. 19 20 26. Vinograd J. 521. Vinokur E. 258 295. Vipond P. W. 89. Visser F. R.,316. Visser H. D. 279. Viswanathan N. 470,472. Vitali D. 100. Vitols E. 560 561. Vitullo V. P. 66 67 334. Vitzthum G. 299 309. Vivamu W. O. 100. Vlattas I. 483 525. v. Nagel R. 290. Vogtle F. 351 465. Voelter W. 41. Vogel A. 353. Vogel E. 32 101,309,353 354. Vogel V. L. 20 23. Vogler V. 15. Volger H. C. 323 401. Volkein G. 421. Vollhardt K. P. C. 303 349 354 359 445 464. Vollmer J. J. 153 315. Volman D. H. 19 27. Vol'pin M. 243 281 306. Volz M.568. von Glehn M. 59. von Hippel P. H. 493. von Kurten S. 417. von Phillipsborn W. 366 398. von Stetten E. 535. von Tigerstrom R. 498. Voorhees R. L. 296. Voronkov M. G. 271. Voroshchenko A. T. 387. Voss J. 32. Vostokov I. A. 279. Vrieze K. 323. Vyazankin N. S. 279. VystrCil A. 419. Wa C. Y. 320. Waali E. E. 369. Wachs T. 7. Waddell T. G. 40. Waddington C. H. 490. Wade A. M. 164. Wade R. C. 28 1. Wadsworth E. M. 130. Wadsworth W. 81 131. Waegell B. 370 373. Waern K. 527. Wagner E. 172 274 275 291. Wagner F. 558. Wagner H. 62. Wagner H. U. 157. Wagner J. 433. Wagner J. S. 294. Wagner 0.W. 564. Wagner P. J. 202 502. Wagniere G. 37. Wagnon J. 425 426. Wahba M. 70. Wahhab S.A. 70. Wahl G. H. 366. Author Index Waits H. P. 183. Wajer Th. A. J. W. 34. Wakabayashi T. 416. Wakamatsu H. 322. Wakefield B. J. 333. Wakselsman M. 81. Walborgsky H. M. 137 238 256 259 291 324. Waldman M. C. 297. Walker D. C. 207. Walker F. W. 278. Walker G. A. 558. Walker J. A. 161 343. Walker P. M. B. 520. Walker R. W. 529. Walker T. J. 203. Walker W. E. 319 321. Wall R. T. 533. Wallace S. C. 207. Wallbridge M. G. H. 287. Wallenfels K. 570. Waller G. R. 468. Walling C. 183 277. Wallis S. R. 37 41 42. Walsh M. J. 471. Walsh R. 169. Walsh T. D. 172. Walter M. 553. Walter W. 32. Walthew J. M. 473. Walton D. R. M. 96 97 274 295 330. Wan J. K. S. 35. Wander R. 209. Wang H.317. Wang J. C. 520. Wang S. F. 574. Wang S. Y. 58 501 502. Ward B. 18 177. Ward G. A. 180. Ward J. F. 213. Ward J. S. 306. Ward L. 573. Ward P. 34. Ward R. 514. Ward R. S. 304. Ward T. J. 182 341. Warhurst E. 25. Waring M. 521. Waring M. J. 500. Warkentin J. 79. Warner C. M. 297. Warner P. 329. Warnick A. 213 505. Warrener R. N. 158 379 396 462. Washburn W. N. 138,139 346. Washburne S. S. 147,280 297. Washecheck P. H. 413. Wasif S. 80. Author Index Wassenaar S. 162. Wasserman E. 317 401. Wasserman H. H. 156 261 342 444 464. Watanabe H. 236. Watanabe K. 334. Watanabe S. 518. Wataya Y. 493. Waters J. M. 59. Waters T. N. 57 59. Waters W. A. 26 33 35 338.Waters W. L. 247. Waterson J. 517. Watkins S. F. 46. Watkinson I. A. 571. Watson D. G. 45. Watson H. C. 57. Watson K. 515. Watson T. G. 419. Watts C. R.,163 348 391 463. Watts G. B. 282. Watts. W. E. 314. Wawzonek S. 234 237. Way J. E. 527. Webb J. L.. 238. Weber G. 41 1,412. Weber H. 490. Weber H. P. 169 428. Weber W. P. 292. Weedon B. C. L. 40 236 527. Weeks C. M. 62. Weeks D. P. 69. Wehmann A. T. 325. Weigert F. J. 366. Weil J. A. 30 267. Weiler L. 259. Weiler-Feilchenfeld H. 347. Weinberg N. L. 186 223 227. Weinblum D. 501. Weiner H. 570. Weiner S. A. 26. Weingarten H. 30 228 294. Weinheimer A. J. 15 41 3 431. Weininger S. J. 328 371. Weinshenker N. M. 190 525.Weinstein J. 35. Weinstein S. 13. Weintraub P. M. 446. Weirenga W . 1 14. Weis. G. B. 510. Weisbach J. A. 529. Weisenborn F. L. 419. Weisgraber K. H. 227. Weisgras J. M. 493. Weiss D. S. 200. White G. F. 83. Weiss E. 276. White J. C. B. 49. Weiss J. 21 3. White J. D. 418. Weiss R.,45. White J. G. 157. Weiss R. I. 359. White P. Y. 11. Weiss S. G. 227. White R.M. 31. Weissbach H. 558 564. White W. N. 80. Weissenberger H. W. O. Whitehouse D. 547. 438. Whitehouse R.D. 39,428. Weissman S. M. 512. Whitesides G. M. 245 Weissmann C. 490 515. 280 310 318 333. Welby-Gieusse M. 524 Whitham G. H. 377. 532. Whiting D. A. 350 479 Welch W. J. 491. 556. Welcher M. 493. Whiting M. C. 1 11,447. Wellington J. L. 202 502.Whitlock H. W. jun. Wellum G. R. 282. 426. Welvart Z. 450. Whitten C. E. 264 310. Wendler N. L. 526. Wiberg K. B. 122 168. Wendt G. 533. Wicker K.,454. Wenkert E. 379 413 469 Wickner R. B. 565. 483. Widdowson D. A. 15,246 Wennig R.,418. 254 474 544. Wentland M. P. 442. Wiebers J. L. 13 497. Wentland S. H. 261. Wiechert R.,424. Wentrup C. 80 457. Wieland D. M. 264. Wenzl R.,309. Wieland P. 427. Werner. H. 308 369. Wierzchowski K. L. 502. Werner P. E. 59. Wiesner K. 485 486. Werthemann L. 252 528. Wife R. L. 358. Wesley D. P. 136. Wigfield D. C. 384. West B. O. 305. Wiggins D. E. 72. West D. E. 343. Wightman R. H. 498. West P. R.,188. Wilbur D. 24. West R. 33 290 295 344 Wilcox C. F. 341. 347. Wild S. B. 305. Westberg H.H. 159. Wilday P. S. 149. Westfelt L. 407. Wilde A. M. 25. Westheimer F. H. 496 Wildman W. C. 55 475 572. 477. Westley J. W. 552. Wildsmith E. 171 398. Westmoreland T. D. 286. Wiley P. F. 493. Weston A. F. 268. Wilke G. 306 323 378. Westphal O. 530 531. Wilkins M. F. H. 490. Westwood R. 90 433. Wilkinson G. 273 310 Wettack F. S. 195. 31 1 322 399. Wetzel R. B. 337. Wilkinson S.,473. Weyenberg D. R.,293. Willard G. F. 179. Weyler W. 334. Willemsens L. C. 297. Whalen D. L. 158 316 Willhalm B. 403. 400. Willi A. V. 67. Whalley E. 107. Williams D. H. 10 11 Whalley W. 253 377. 304. Whalley W. B. 62 424. Williams D. H. L. 148. Wharf I. 241 31 1. Williams D. J. 360. Wheeler T. N. 427. Williams D. R. 30. Wheland R.,154,389,436. Williams F.T. 65 136. Whistance G. R.,555. Williams G. H. 182 338. White A. F. 413 539. Williams J. E. 365. White A. M. 66 116. Williams J. L. R.,282. White D. C. 531. Williams K. C. 297. White D. V.. 156. Williams L. T. 23. Williams R. 563. Williams R. E. 271. Williams R. J. P. 564. Williams R. M. 113. Williams W. G. 31. Williams V. Z. 122 382. Williamson K. L. 428. Willing R. 1.,467,475,486. Willis B. T. M.,51 162 251. Willson R. L. 208 209 213 214 215 216 217. Wilson B. A. 182 338. Wilson B. J. 544. Wilson E. R. 219. Wilson F. B. 53. Wilson H. R. 58. Wilson J. D. 30 228. Wilson J. M. 63. Wilson K. E. 242. Wilson M. A. 149. Wilson R. 24 28. Wilson R. L. 505. Wilson W. S. 462. Wilt J.W. 107 295 343. Wilton D. C. 571. Wilzbach K. E. 197. Win F. T. 129. Winer A. D. 568. Winkler J. 12. Winkley M. W. 37 496 497. Winstein S. 101 104 105 107 108 109 115 116 119 141 164 168 328 329 393. Winterfeldt E. 146. Wirthwein R. 341. Wiseman J. R. 379. Wiskott E. 382. Witkin E. M.,490. Witkop B. 486. Witt D. R. 31 I. Wittig G. 344. Wladislaw B. 221. Woenckhaus V. C. 569. Woerner F. P. 446. Woese C. 51 I. Wojcicki A. 321. Wolf A. P. 172 381. Wolf R. 118. Wolf R. E. 244 383. Wolf W. 29. Wolfe R. G. 569. Wolfe S. 136 250 437. Wolff H. P. 307. Wolff R. E. 12 Wolff R. K. 207. Wolff T. 427. Wolfgang R. L. 381. Wolinsky J. 362 404. Wolovsky. R. 317 401. Wolters J. 332. Won C.M.,67. Wonacott A. J. 497 567. Wong K. H. 274. Wong L. Y. 182. Wong S. K. 9. Woo E. P. 310 355. Wood D. E. 18 26. Wood H. C. S. 556. Wood L. S. 172. Wood N. F. 301. Woodcock D. J. 104. Woodgate P. D.. 8 12. Woodlock A, 49. Woods R. 236. Woods W. G. 272. Woodward P. 46. Woodward R. B. 37 153 162 205 315 391. Worth G. K. 417. Wriede P. A. 200. Wright G. J. 331. Wright J. R. 408. Wright L. H. 54. Wright M. 377. Wriglesworth M.J. 421. Wrixon A. D. 38 367. Wrobel J. T. 546. Wu C. S. 486. Wu R. 520. Wubbels G. W. 199. Wudl F. 30. Wuensch K. H. 205. Wunsche. C.. 9. Wuepper J. L. 286. Wuesthoff M. T. 384. Wuthrich K. 368. Wulff G. 453. Wyatt P. A. H. 63. Wyckoff H. 496. Wyckoff J.C. 262. Wylie W. A, 100. Wynberg H. 198 445. Wyvratt M. J. 157. 437. Yablonskii 0.P. 3 17. Yagupsky G. 273 310 311. Yagupsky M. 31 I. Yakhontov L. N. 330. Yakubchik A. I. 31 I. Yakushi K. 48. Yalpani M. 250. Yamachica N. J. 150. Yamada C. 204. Yamada E. 105 180. Yamada T. 490. Yamada Y. 469,494. Yamaji M. 325. Yamamoto A. 3 17. Yamamoto H. 139 253 258 303 41 1 527 528. Author Index Yamamoto K. 293 297. Yamamoto O. 533. Yamamoto S. 541. Yamamoto Y. 322. Yamamura J. 412. Yamamura Y. 531. Yamanaka Y. 471. Yamane H. 474. Yamaoka K. 42. Yamatani T. 343. Yamato E. 260. Yamazaki H. 319 322. Yan T. C. 420. Yanagawa H. 246. Yanase R. 526 527. Yandovskii V. N. 436. Yang E.M. 524. Yang K.-W. 260. Yang S. S. 516. Yanina A. D. 330. Yaniv M. 508 510. Yankee E. W. 139 383. Yano I. 529. Yano K. 403. Yano Y. 142 143. Yanofsky C. 518. Yanuka Y. 430. Yastrebova G. E. 273. Yasuda H. 287. Yasuda S. 504. Yasunami M. 343. Yasuoka N. 287. Yasuraoka Y. 67. Yates K. 65. Yazawa H. 250. Ydelevich A, 508. Yeager S. A. 275 344. Yee K. C. 136 142 385. Yee T. 423. Yendra A. J. 367. Yeo,A. N. H.. 10 11. Yip R. W. 202. Yokoyama H. 40. Yokozeki A. 373. Yonei S. 504. Yonezawa T. 19 133. Yoon N. M. 243. Yoshida A. 518. Yoshida K. 226. Yoshida M. 21 181 244 266 340 5 10. Yoshida T. 406 Yoshida Z. 172 382 439. Yoshifuji M. 331. Yoshihara H. 504. Yoshihira K.359. Yoshikawa M. 491. Yoshikoshi A, 379 41 1. Yoshioka H. 407 408. Yoshioka M. 429. Young D. W. 58. Author Index Young G. A. R. 414. Young G. W. 280. Young J. D. 509. Young R.N. 274,276. Youngblood W. W. 413. Yournas M. 81 100. Yourno J. 5 18. Yousif G. 90. Ysizin. Y. S. 407. Yu S. H. 277 287. Yu T. T. J. 469. Yuh Pan Chen 417. Yurchenko A. G. 387. Zabarski 0. R. 152. Zacharis H. 45. Zahner H. 15. Zagalak B. 559. Zahra J. P. 370. Zajacek J. G. 247. Zalewski R. I. 64. Zamecnik I. 41 2. Zamir A. 498. Zappia V. 562. Zarandy M. S. 96. Zimmermann J. P. 221. Zarkowsky H. 574. Zinbo M. 12. Zbiral E. 248. Zingaro R. A. 32. Zdunnek P. 284. Ziondron C. 104. Zecher D. C. 33 344.Zivanov D. 430. Zechmeister K. 60 417. Zmudzka B. 505. Zeiss H. H. 278. Zollinger H. 91 92. Zelawski Z. S. 526. Zon G. 302. Zeldes H. 20 23. 28. Zondler R. 458. Zeleska H. J. 250. Zsindely J. 335. Zelesko M. J. 288. Zubay G. 522. Zelnik R.,419. Zubiani G. 251 277. Zemlyanskii N. N. 298. Zubiani M. G. 258. Zepp R. G. 184,436. Zucchini U. 310. Zhidimorov G. M. 19. Zuckerman B. 491. Zhmurova I. N. 304. Zuckerman J. J. 273. Zigman A. R. 234. Zuech E. A. 316. Ziegler F. E. 482. Zurcher W. IS. Ziffer H. 14 40 201. Zurzur J.-M. 22. Zilg H. 555. Zwanenburg E. 169. Zimbrick J. D. 213 505. Zweifel G. 244 285. Zimmerman H. E. 166 Zwierzak A. 254. 197 203 341. Zymalkowski F. 417. Zimmerman J. J. 73.

ISSN:0069-3030    

DOI:10.1039/OC9706700577

出版商:RSC    

年代:1970

数据来源: RSC

摘要:

SUBJECT INDEX Acetylene cyclotrimerisation 3 18. Acid-base catalysis 66. Acidity functions 63. Addition reactions to unsaturated systems 145. Aflatoxin B ,540. Alicyclic compounds cycloaddition reactions 3 8 8. reactions 382. structure and conformation 365. synthesis 374. thermolysis 391. transition-metal reactions 399. Alicyclic large rings synthesis 376. Alicyclic systems kinetics and mechanism 110. Aliphatic acids oxidative decarboxylation 189. Aliphatic systems kinetics and mechanism 113. Alkali-metals organometallic compounds 276. Alkenes cathodic reactions of 232. Alkylarenes oxidation of 19 1. Alkylation 262. Alkylbenzenes metallation 264. Aluminium hydride reductions 242. Aluminium organometallic compounds 285.Amaryllidaceae alkaloids 475. biosynthesis 548. Annulenes 350. Anodic reactions 219. carboxylates 2 19 220. neutral organic molecules 222. organic anions 2 19. Antimony organometallic compounds 304. Aqueous organic systems pulse radiolysis studies 208. Aromatic compounds X-ray studies 45. Aroyl radicals 178. Arsenic organometallic compounds 304. Aryl ketones photoreduction 196. Aspidosperma and Iboga alkaloids 482 Azo-compound thermal decomposition 187. Backbone rearrangements in steroids 425. Baeyer-Villiger reaction 248 249. Barton reaction 422 424. Bases nucleosides and nucleotides 492. Benzene and derivatives 330. Benzene isomers 340. Benzoyl radical 177. Benzynes 340. Beryllium organometallic compounds 276.Bicyclic systems reactions 385. structure and conformation 372. synthesis 379. Bimolecular displacements kinetics and mechanism 129. Biological and biochemical systems pulse radiolysis studies 21 3. Biological X-ray studies 57. Bismuth organometallic compounds 304. Boron hydride reductions 243. Boron organometallic compounds 282. Branched-chain fatty acids synthesis 527. Cadmium organometallic compounds 279. Camphor biosynthesis 537. Carbanions and enolisation 133. Carbene complexes of transition metals 307. Carbene insertion 321. Carbenes mechanisms of reactions 172 Carbon- 13 labelling 549 550 55 I. Carbon-carbon double bond isomerisa-tion 313. Carbon skeletal rearrangement 314. Carbonium ions in solvolytic reactions 101.Carbonyl compounds cathodic reactions 235. methods of preparation 255. Carbonyl reactions kinetics and rnecha-nism 150. Carbonylation in synthesis 322. Carboxylic acids general preparations of 259. Catalytic hydrogenation 241. Cathodic reactions 23 1. of alkenes 232. of aromatic compounds 232. of carbonyl compounds 235. miscellaneous 239. of organic cations 231. Charge-transfer processes 196. Cheletropic processes mechanisms 170. Chemically induced dynamic nuclear pola- risation 179. Chiroptical techniques 36. Cholesterol biosynthesis 540. Circular dichroism 36. Clathrates X-ray studies 52. Co-dimerisation 320. Coenzyme B * 558. mechanism 563. n-Complexes 3 19.a-Complexes. 3 10. Configurational assignments from 0.r.d. and c.d. 40. Conformational studies solvent and tem- perature dependence 41. Corynanthh-Strychnos alkaloids 480. Cotton effect 36. Coupling methods 262. Crownanes 245. Crystallographic studies 43. Cyanolipids 532. Cycloaddition reactions 2 +2 388. 4+2 389. mechanisms 154. Cycloalkane acids synthesis 525. Cyclophanes 350. Cyclotrimerisation of acetylenes 3 18. DNA 519. Decarboxylation in synthesis 323. Dehydrogenases structure 567. Diacyl peroxides 183. Diazomium salts 180 181. Dienone rearrangements 197. Dimerisation of olefins 3 17 3 19. Di-n-methane rearrangements 201 202. Diol lipids 529. Dioldehydrase 558. Dioxetan formation 204.Displacement reactions kinetics and mechanisms 13 1. sites other than carbon 131. Diterpere biosynthesis 539. Diterpenoids 41 3. Ecd}sone synthesis 430. Hectrocyclic reactions mechanisms 168. Election spin resonance flow systems 28. halogen splittings 22. hyperfine splittings 18. kinetics 23. linewidths 23. photolysis 27. proton splittings 19. relaxation 23. E.s.r. spectra anion radicals 30. cation radicals 29. nitroxides 33. short-lived radicals 27. stable radicals 29. Electro-organic chemistry 21 9. practical innovations 240. Electrophilic aromatic substitution 90. Electrophilic attack on co-ordinated ligands 325. Elimination reactions kinetics and mech- anism 141. Subject Index Enzyme catalysis 557.Enzyme mechanisms 557. Ergot alkaloid biosynthesis 543. Ester hydrolysis 80. Ethanol deaminase. 560. Fatty acids 523. isolation and structure 523. reactions 528. synthesis 524. Five-membered rings reactions 384. structure and conformation 368. synthesis 376. Four-membered rings reactions 382. structure and conformation 368. synthesis 375. Fragmentation processes in mass spectro- metry 10. Free-radical reactions 177. Furan photodecomposition 199. Gallium organometallic compounds 285. Germanium organometallic compounds 289. Gossypol biosynthesis 538. Gibberellin biosynthesis 539. Glutamate mutase 562. Glycerol dehydrase 560. Glycerol lipids 529. Glycolipids 53 1. Grignard reagents 277.Halogens reductive cleavage 238. Heterocyclic compounds 433. five-membered rings with one hetero-atom 440. with two or more hetero-atoms 446. four-membered rings 437. seven-membered and larger rings 460. six-membered rings nitrogen derivatives 449. oxygen derivatives 452. sulphur derivatives 452. with two or more hetero-atoms 456. three-membered rings 433. X-ray studies 49. Homoaromaticity 328. Homogeneous reduction of functional groups 310. Hydrocarbon complexes of transition metals 306. Hydrogen bonding X-ray studies 52. Hydrogen exchange reactions 3 10. Hydrogenation of carbon-carbon unsatura- tion 310. Hydrosilylation of olefins 312. Indium argonometallic compounds 285. Indole alkaloids 478. biosynthesis 542.Subject Index Insertion reactions organometallic com-pounds 321. Intermolecular hydrogen exchange 3 12. Intramolecular oxidative addition 3 12. Ion cyclotron resonance spectroscopy 7. Ion energies from mass spectrometry 7. Ion kinetic energy spectroscopy 7. Ion structures from mass spectrometry 7. Ionones 201. Isomerisation of C =C 31 3. Isomerisation of the carbon skeleton 314. lsoquinoline alkaloids 47 1. biosynthesis 544. Kinetics acid-base catalysis 66. electrophilic aromatic substitution 90. ester hydrolysis 80. nucleophilic aromatic substitution 97. solvolytic reactions 107. substituent effects 96. Kinetics and mechanisms alicyclic systems 110. aliphatic systems 1 13. carbonyl reactions 150.elimination reactions 141. neighbouring groups 132. norbornyl systems 11 5. rr-participation 107. small rings 12 1. vinyl cations 125. Kolbe reaction 2 19. Lead organometallic compounds 296. Linear free-energy relationships 96. Lithium organometallic compounds 274. Loganin biosynthesis 536. Lupin alkaloids 469. L-@-Lysine mutase 562. Magnesium organometallic compounds 277. Magneto-optical techniques 42. Mass spectrometry interpretative methods 7. Meisenheimer rearrangement 179. Mercury organometallic compounds 280. Mesembrine alkaloids 477. Metallation of alkylbenzenes 264. Methylmalonyl CoA mutase 561. Mevalonic acid biosynthesis 535. Molecular basicity 63. Monoterpenes 403. biosynthesis 536.Multicyclic compounds X-ray studies 43. Mycolic acids 524. Natural products X-ray studies 54. Neighbouring-group participation kinetics and mechanism 132. Nitrenes mechanisms of reactions 174. Non-aqueous organic systems pulse radio- lysis studies 21 1. 621 Non-benzene systems 344 341. Norbornyl systems kinetics and mech-anism 115. Normal-chain fatty acids synthesis 524. Norrish reactions 195 199. Nucleic acids pairing and stacking 505. Nucleophilic aromatic substitution 97. Nucleophilic attack on co-ordinated ligands 324. Nucleosides 492. Nucleotides 492. Octant Rule 37. Olefins dimerisation 3 17 3 19. disproportionation 3 16. hydrosilylation 3 12. reactions 253. synthesis 25 1. Oligomerisation of unsaturated hydrocar- bons 3 17.Oligonucleotides 497. Optical rotatory dispersion 36. Orbital symmetry correlations 153. Organic cations cathodic reactions 23 1. Organo-sulphur compounds 309. Oxetan formation 200. Oxidation methods 246. Pairing and stacking conformations of nucleic acids 505. Pericyclic processes mechanisms 170. Phosphorus organometallic compounds 300. Photochemistry 195. of aromatic systems 197. of nucleic acids 501. Photo-Fries reaction 199. Photonitrosation of hydrocarbons 205. Phthiocerols 53 1. Piperidine alkaloid biosynthesis 545. Poiycyclic systems 355 reactions 387. synthesis 381. Polyfluorophenyl radicals 182. Polyketide biosynt hesis 548. Prebiotic chemistry 491. Prostaglandins synthesis 525.Prosthetic groups 564. Protein biosynthesis 516. Pulse radiolysis studies aqueous organic systems 208. biological and biochemical 21 3. non-aqueous organic systems 2 1 1. pyrimidines 2 1 3. reactive intermediates 207. Pyridine alkaloids 468. Pyridine nucleotides 566. active site groups 567. conformation 566. geometry of the active site 570. role in C =C reduction 570. 622 Subject Index role in carbohydrate transformations Stilbene photocyclisation 199. 572. Substitution nucleophilic aromatic 97. Pyrimidines pulse radiolysis studies 2 13. Sulphate radical-ion 188. Pyrrolizidine alkaloids 467. Sulpholipids 532. biosynthesis 547. Symmetrical chromophores regional rules 37. Quenching data 195.Quinoline alkaloids 469. Thallium organometallic compounds 285. Thermolysis alicyclic compounds 391. RNA 507. Three-membered rings Radical pairs 178. reactions 382 Reactive intermediates pulse radiolysis structure and conformation 368. studies 207. synthesis 375. Rearrangement processes in mass spectro- Thujone biosynthesis 537. metry 10. Tin organometallic compounds 296. Reduction methods 241. Transition metals catalysis of reactions of Reductive cleavage of halogens 238. alicyclic compounds 399. Regional rules for symmetrical chromo-Transfer RNA 508. phores 37. Tricodermol biosynthesis 537. Ribonucleotide reductase 560. Tricothecane antibiotics 537. Ribosomal RNA 512. Tricyclic systems structure and conforma- Ring compounds X-ray studies 43.tion 372. Triterpenes 4 19. Schenck mechanism 195 196. Sesquiterpenes 407. biosynthesis 537. Unsaturated ketones 201. Sesterterpenoids 419. Unsaturated systems addition reactions Seven-membered rings structure and con- 145. formation 370. Sigmatropic reactions mechanisms 163. Vinyl cations kinetics and mechanism 125. Silicon organometallic compounds 289. Viral RNA 512. Singlet oxygen addition 204. Six-membered rings reactions 384. Wessely reaction 248. structure and conformation 368. Wilkinson’s catalyst 241. synthesis 376. Skeletal rearrangements Wittig reaction 257. of alkaloids 483. of carbon chains 3 14 X-Ray crystallography Small ring compounds kinetics and mech- aromatic compounds 45. anisms 121. clothrates 52. Sodium organometallic compounds 276. heterocyclic compounds 49. Solvolytic reactions multicyclic compounds 43. carbonium ions in 101. natural products 54. kinetics and mechanisms 106. ring compounds 43. Sphingolipids 530. Steroids 424. biosynthesis 540. Zinc organometallic compounds 279.

ISSN:0069-3030    

DOI:10.1039/OC9706700619

出版商:RSC    

年代:1970

数据来源: RSC