15 Biological Chemistry Part (i) Biosynthesis By J. R. HANSON School of Molecular Sciences University of Sussex Brighton BN 1 9QJ Despite the fact that only a two-year period has elapsed since the last Report,’ the volume of published work necessitates a highly selective treatment of secondary metabolism. Many of the advances depend on n.m.r. methods in which high-field spectrometers have made a significant contribution. An interesting article2 describes n.m.r. methods for tracing the fate of hydrogen in biosynthesis. Some stereochemical consequences of enzymic reactions particularly at allylic carbon atoms have been reviewed in a published le~ture.~ The stereochemistry of allylic pyrophosphate metabolism which plays an important role in terpenoid cyclizations has also been e~arnined.~An extensive review has appeared5 on chiral methyl-group methodology.1 Polyketide Biosynthesis Arachidonic acid (1) has been shown to be a key precursor not only for the biosynthesis of the prostaglandins and thromboxanes,6 but also uiu 5-hydroperoxy-eicosatrienoic acid (5-HPETE)(2),of the leukotrienes A (3) and the ‘slow reacting I substances of anaphylaxis’ (SRS-A’s) leukotrienes C-1 (4; R = Glu-Cys-Gly) D I I (4; R = Cys-Gly) and E(4;R = CYS).~ The biosynthesis of the unusual unsaturated acid (2E,4E,6E)-5-(acetoxy-methyl)tetradeca-2,4,6-trienoicacid formed by the plant Eremophilu oppositifoliu has been shown’ to follow the acetate:malonate pathway. Studies on the biosynthesis of [6]-ginger01 (9,which is a pungent principle of ginger (Zingiber oficinale) have demonstrated’ that it arises from dihydroferulic acid malonate and hexanoic acid.’ J. R. Hanson Annu. Rep. Prog. Chem. Sect. B 1978,75,329. * M. J. Garson and J. Staunton Chem. SOC. Rev. 1979 8 539. K. H. Overton Chem. SOC. Rev. 1979,8,447. D. E. Cane Tetrahedron 1980 36 1109. H. Floss and M.-D. Tsai Adv. Enzymol. 1979,50 243. ‘P. R. Marsham in ‘Aliphatic and Related Natural Product Chemistry’ ed. F. D. Gunstone (Specialist Periodical Reports) The Chemical Society London 1979,Vol. 1,p. 170. ’S. Hammarstrom B. Samuelsson D. A. Clark G. Goto A. Marfat C. Mioskowski and E. J. Corey Biochem. Biophys. Res. Commun. 1980,92 946; ibid. 1980 94 1133. E. L. Ghisalberti P. R. Jefferies and R.F. Toia Phytochemistry 1979.18 65. I. MacLeod and D. A. Whiting J. Chem. SOC. Chem. Commun. 1979,1152; P. Denniff I. MacLeod and D. A. Whiting J. Chem. SOC.,Perkin Trans 1 1980 2637. 289 290 J. R. Hanson H-OOH +C02H OH (6) -and = [13C2]acetatecoupling A computer optimization of the 13Cn.m.r. FID data has enabled" a two-bond C-I3C coupling (C-2-C-8) to be detected in asperlactone (6) that had been biosynthesized from [1,2-13C2]acetate and thus it was established that these two carbon atoms have their origin in the same [13C2]acetate unit. This sophisticated application of 13C n.m.r. techniques promises to have quite wide application in detecting rearrangements. The biosynthesis of citrinin (8) by Penicillium citrinum has continued to attract attention and has also been the subject of several n.m.r.studies. Evidence concern- ing the origin of the hydrogen atoms in citrinin has been obtained by producing the metabolite from protium-labelled carbon sources on a deuterium oxide medium." The methylation steps appear to precede'* the formation of the aromatic ring. Deuterium-labelling ~tudies'~ have shown that the aldehyde (7) plays an important role in the biosynthesis. A sequence based on the feeding of potential late precursors has been proposed.14 Ascochitine (9) is a phytotoxic metabolite of Ascochytu fabae in which methylation of the polyketide chain also appears" to precede aromatization. & HO/ \ O&-H02C \ \ 0 H02CH O\o W OH CHo OH 0 (7) (8) (9) lo R.G. Brereton M. J. Garson and J. Staunton J. Chem. SOC., Chem. Commun. 1980 1165. R. H. Carter M. J. Garson and J. Staunton J. Chem. SOC., Chem. Commun. 1979 1097; J. Barber and J. Staunton ibid. p. 1098; J. Barber and J. Staunton J. Chem. SOC.,Perkin Trans. I 1980 2244. J. Barber and J. Staunton J. Chem. SOC., Chem. Commun. 1980 552. l3 J. Barber and J. Staunton J. Chem. SOC., Chem. Commun. 1980 1163. l4 L. Colombo C. Gennari F. Aragozzini and C. Merendi J. Chem. SOC., Chem. Commun. 1980,1132. '*L. Colombo C. Gennari G. S. Ricca C. Scolastico and F. Aragozzini J. Chem. SOC., Perkin Trans. 1 1980 675; L. Colombo C. Gennari C. Scolastico F. Aragozzini and C. Merendi ibid. p. 2549. Biological Chemistry -Part (i) Biosynthesis 291 The detection of l8Olabels by studying the isotope effect on 13C n.m.r.shifts has been used16 in determining the origin of the oxygen atoms in the biosynthesis of averufin (10).The conversion of averufin into the mycotoxin aflatoxin Bt (11)has been examined," using material biosynthesized from [1,2-13C2]acetate. Full papers have appeared on the role of versiconal acetate in aflatoxin biosynthesis," on the biosynthesis of the mycotoxin ochratoxin A,19 and on the phenalenone metabolites of Penicillium herquei.*' (10) (11) (12) R = H02C-A/ (14) R = H02C In a study of the biosynthesis of mycophenolic acid (12) by Penicilliurn brevicorn- pactum it has been that the farnesylphthalide (13)and the prenylogue of mycophenolic acid (14) are formed under conditions commensurate with their probable role in the biosynthesis.2 Terpenoids and Steroids Considerable attention has been on prenyl transferase (the enzyme system responsible for the oligomerization of isoprene units) and on the mechanism of the coupling reaction in terpenoid bio~ynthesis,~~ whilst the substrate specificity l6 J. C. Verderos and T. T. Nakashima J. Chem. SOC.,Chem. Commun. 1980 183. 17 A. E. De Jesus C. P. Gorst-Allman P. S. Steyn R. Vleggaar P. L. Wessels C. C. Wan and D. P. H. Hsieh J. Chem. SOC.,Chem. Commun. 1980,389. IS P. S. Steyn R. Vleggaar P. L. Wessels and De Buys Scott J. Chem. SOC.,Perkin Trans. I 1979,460. l9 A. E. De Jesus P.S. Steyn R. Vleggaar and P. L. Wessels J. Chem. SOC.,Perkin Trans. 1 1980 52.2o T. J. Simpson J. Chem. SOC.,Perkin Trans. 1 1979 1233. 21 L. Colombo C. Gennari D. Potenza C. Scolastico and F. Aragozzini,J. Chem. SOC., Chem. Commun. 1979,1021. 22 D. L. Doerfler L. A. Ernst and I. M. Campbell J. Chem. SOC.,Chem. Commun. 1980 329. 23 H. C. Rilling Pure Appf. Chem. 1979 51 697. 24 C. D. Poulter E. A. Marsh J. Argyle 0. J. Muscio and H. C. Rilling J. Am. Chem. SOC. 1979 101,6761. 292 J. R. Hanson of farnesyl pyrophosphate synthetase has also been e~amined.~’ The C-10-methyl group (trans to the chain) of geraniol has been shownz6 to arise from C-2 of mevalonate. In the redox interconversion of geraniol and nerol the 1-pro-S hydro- gen atom appearsz7 to be lost in the formation of nerol whereas the reverse isomerization involves the loss of the 1-pro-R atom.Some evidence has been presentedz8 supporting the preferential participation of linaloyl rather than neryl pyrophosphate in the biosynthesis of cyclic monoterpenoids in higher plants. The oxidation of limonene to carvone in Me;ztha spicata a shift of the endocyclic double-bond whilst studies on the biosynthesis of the carane skeleton show3’ that it is constructed from its monocyclic precursor with the migration of the double-bond and an unexpected 1,2-shift of a proton to the site of the original double- bond. The enzymatic conversion of farnesyl pyrophosphate into nerolidyl pyrophos- phate and the role of the latter in the biosynthesis of cyclonerodiol has been examined.31 [G-13C6]G1~~ose has been as a source of acetate units in a study of the biosynthesis of pentalenolactone (16),with results suggesting that the carbon skeleton arises by the folding of farnesyl pyrophosphate (15) as shown.Deuterium n.m.r. methods have been used to define the fate of mevalonoid hydrogen atoms in the biosynthesis of fomanno~in,~~ and dihydr~botrydial.~~ capsidi01,~~ Studies on the enzymatic biosynthesis of ent-~andaracopimaradiene~~ and of ent-ka~rene,~~ using stereospecifically labelled geranylgeranyl pyrophosphate and copalyl pyrophosphate (17) have shown that the cyclization of the latter occurs with anti stereochemistry. The labelling of ring D of ent-kaurene (18) by [3,6-(17) (18) ” T. Koyama A. Saito K. Ogura and S. Seto J. Am. Chem. SOC. 1980,102 3614.A. Akhila and D. V. Banthorpe Phytochemistry 1980 19 1429. 27 D. V. Banthorpe and I. Poole Phytochemistry 1979 18 1297. 28 T.Suga T. Shishibori and H. Morinaka J. Chem. SOC. Chem. Commun. 1980 167. 29 A. Akhila D. V. Banthorpe and M. G. Rowan Phytochemistry 1980,19 1433. 30 A. Akhila and D. V. Banthorpe Phytochernistry 1980,19 1691. 31 D.E.Cane and R. Iyengar J. Am. Chem. SOC. 1979,101,3385. 32 D. E.Cane T. Rossi and J. P. Pachlatko Tetrahedron Lett. 1979 3639. 33 D.E.Cane and R. B. Naschbar Tetrahedron Lett. 1980 21 437. 34 Y. Hoyano A Stoessl and J. B. Stothers Can. J. Chem. 1980,58 1894. 35 A. P.W. Bradshaw and J. R. Hanson J. Chem. SOC. Chem. Cornmun. 1979,924. 36 K.A. Drengler and R. M. Coates J. Chem. SOC. Chem. Commun. 1980,856. 37 R.M.Coates and P.L. Cavender J. Am. Chem. SOC. 1980,102,6358. Biological Chemistry -Part (i) Biosynthesis '3C2]mevalonolactone is with the currently accepted biosynthetic scheme. ent-Kaur-15-ene rather than the normal gibberellin plant hormone inter- mediate ent-kaur-16-ene is by dwarf-5 mutants of maize whilst ent- kauran 16@,17-epoxide is an inhibitor of the biosynthesis of gibberellic acid.40 The biosynthesis of the secokauranoid enmein41 and the relationship of the kaurenol- ides4* in Gibberella fujikuroi have been examined whilst the lack of substrate specificity of G. fujikuroi has also been used to prepare biosynthetically pentacyclic analogues of the gibber ell in^,^^ ati~agibberellins,~~ and fl~orogibberellins.~~ Studies of the substrate specificity of lanosterol-2,3-oxidosqualene cyclase have the requirement for an epoxide and at least two appropriately oriented double-bonds.(RS)-Epoxysqualene has been cy~lized~~ by various cell-free systems to mixtures of 3a- and 3P -hydroxy-triterpenes. The incorporation of a 3P-hydrogen atom in the non-oxidative cyclization of squalene in tetrahymanol biosynthesis has been studied,48 utilizing *H n.m.r. Incubation49 of 14a-(hydroxymethyl)-5a -cholest-7-en-3P-o1(19) with rat liver microsomes gives 5a -cholest-8( 14)-en-3@ -01 and requires only an NADH/NADPH generator to afford formic acid. The sugges- tion was made that the loss of the hydroxymethyl group occurs by an oxygen- independent process uia dehydrogenation to the 14-aldehyde. The subsequent hydrolytic removal of formic acid may be assisted by the double-bond.Evidence has been presented5' suggesting the possible intervention of the 7a -alcohol 5a-cholest-8( 14)-en-3&7a -diol in the 14a-demethylation reaction. (19) (20) The hydrogen atom at C-28 in the alkylated sterol poriferasterol which arises from S-adenosylmethionine has been shown" to assume the pro-S position whilst the pro-R hydrogen atom comes from the reducing agent. In contrast the C-23 olefinic methyl group of dinosterol retains5' three deuterium atoms from methion- 38 K. Honda T. Shishibori and T. Suga J. Chem. Res. (S) 1980 218. 39 P. Hedden and B. 0.Phinney Phytochemistry 1979,18,1475. 40 J. R. Hanson C. L. Willis and K. P. Parry Phytochemistry 1980 19 2323. T.Fujita S. Takao and E. Fujita J. Chem. SOC.,Perkin Trans. 1 1979 2468. 42 J. R. Hanson and F. Y. Sarah J. Chem. SOC. Perkin Trans. 1,1979,3151. 43 J. R. Bearder J. MacMillan A. Matsuo and B. 0.Phinney J. Chem.SOC.,Chem. Commun. 1979,649. 44 J. R. Hanson F. Y. Sarah B. M. Fraga and M. G. Hernandez Phytochemistry 1979,18 1875. 45 B. E. Cross and P. Filippone J. Chem. Soc. Chem. Commun. 1980 1097. 46 E. E. van Tamelen and R. E. Hopla J. Am. Chem. SOC.,1979,101,6112. 47 M. Rohmer C. Anding and G. Ourisson Eur. J. Biochem. 1980,112 541 48 E. Caspi Acc. Chem. Res. 1980 13 97; D. J. Aberhart and E. Caspi J. Am. Chem. Soc. 1979 101,1013. 49 R. A. Pascal P. Chang and G. J. Schroepfer J. Am. Chem. SOC.,1980,102,6599. M. Galli-Kienle M. Anastasia G.Cighetti G. Galli and A. Fiecchi Eur. J. Biochem. 1980,110 93. 51 F. Nicotra B. M. Ranzi F. Ronchetti G. Russo and L. Toma J. Chem. SOC.,Chem. Commun. 1980 752. '* N. W. Withers R. C. Tuttle L. J. Goad and T. W. Goodwin Phytochemistry 1979 18 71. 294 J R. Hanson ine. Phytophagous insects obtain their dietary cholesterol by the dealkylation of phytosterols such as fucosterol utilizing the (24R,28S)-epoxides but not their (24S,28R)-i~omers.~~ The stereochemistry of hydroxylation of cholesterol at C-22 during pregnenolone biosynthesis occurss4 with retention of configuration to give the (22R)-stereoisomer. The deuterium and carbon-13 enrichment patterns of samples of the fungal metabolite demethoxyviridin (20) derived from labelled acetate and mevalonates are consistent with its triterpenoid origin in which lanosterol rather than cycloartenol is an intermediate.” The structures and labell- ing patterns of the side-chain fragments that the cleavage of the side-chain follows a mammalian rather than a bacterial route.Full papers on the biosynthesis of wortmannin from [1,2-’3C2]a~etate57 and on various lanosterol derivatives as possible intermediates in viridin biosynthesisS8 have appeared. The stereochemistry of elimination of the 12-hydrogen atoms in the formation of olean- and urs-12-enes has been examined.” The chemical and enzymological aspects of the biosynthesis of the carotenoids have been reviewed.60 The stereochemical origin of the C-1-methyl groups of zeaxanthin in the cyclization of carotenoid precursors has been studied by 13C n.m.r.methods.61 3 Shikimic Acid The normal route for tyrosine biosynthesis involves 4-hydroxyphenylpyruvate. However arogenic acid (2l),(pretyrosine) has been shown62 to act as a precursor in some micro-organisms. L-Phenylalanine is a precursor of caffeic acid in Ocimum ba~ilicum.~~ OH (21) (22) The fungal flavanoid chlorflavonin (22) is unusual both as a fungal flavanoid and in its origin via a c& (benzoate) and four acetate A number of stereochemical aspects of the late stages of rotenone biosynthesis and its relation- ship to amorphigenin have been e~amined.~’ Full papers have appeared on the 53 F. Nicotra F. Ronchetti G. Russo and L. Toma J. Chem. SOC.,Chem. Commun. 1980,479.54 C. Duque M. Morisaki N. Ikekawa and M. Shikita Tetrahedron Lett. 1979 4479. 55 J. R. Hanson and H. Wadsworth J. Chem. SOC.,Chem. Commun. 1979,360. 56 J. R. Hanson M. A. O’Leary and H. Wadsworth J. Chem. SOC.,Chem. Commun. 1980,853. ST T. J. Simpson M. W. Lunnon and J. MacMillan J. Chem. SOC.,Perkin Trans. 1 1979,931. 58 W. S. Colder and T. R. Watson J. Chem. SOC.,Perkin Trans. 1 1980 422. 59 S. Seo Y. Tomita K. Tori and Y. Yoshimura J. Chem. SOC.,Chem. Commun. 1980,.1275. 6o T. W. Goodwin Pure Appl. Chem. 1979,51,593; J. W. Porter and S. L. Spurgeon ibid.,p. 609. G. Britton T. W. Goodwin W. J. S. Lockley A. P. Mundy N. J. Patel and G. Englert J. Chem. SOC., Chem. Commun. 1979,27. 62 L. 0.Zamir R. A. Jensen B. H. Arison A. W. Douglas G. Albers-Schonberg and J.R. Bowen J. Am. Chem. SOC.,1980,102,4499. 63 L. Canonica P.Gramatica P. Manitto and D. Monti J. Chem. SOC.,Chem. Commun. 1979 1073. 64 M. K. Burns J. M. Coffin I. Kurobane and L. C. Vining J. Chem. SOC., Chem. Commun. 1979,426. 6s L. Crombie I. Holden G. W. Kilbee and D. A. Whiting J. Chem. SOC.,Chem. Commun. 1979 1143,1144. Biological Chemistry -Part (i) Biosynthesis 295 biosynthetic relationships involved in pterocarpan and isoflavan phytoalexin biosyn- thesis in Medicago sativa and between the aryl-benzofurans of Vigna unguiculata.66 Labelling studies have that the anthraqui,ione lucidin obtained from Galium mollugo arises from 1,4-dihydroxy-3-prenyI-2-naphthoic acid. 4 Alkaloid Biosynthesis The biosynthesis of the alkaloids has been reviewed.68 The 13C-labelling patterns of nicotine and of cocaine bio~ynthesized~~ from ornithine are in accord with a symmetrical precursor for the pyrrolidine ring whilst a symmetrical C4-N-C4 unit derived from ornithine is also implicated7’ in the formation of the retronecine rings of the pyrrolizidine alkaloids The conversion of isoleucine into the necic acids involves the loss of the 4-pro-s hydrogen atom.71 The formation of the simplest of the harman alkaloids (23) involves the decar- boxylation of 1-methyl-1,2,3,4-tetrahydro-~-carboline-l-carboxylic acid.” Stric-tosidine (24) plays a key role in indole alkaloid biosynthe~is.~~ Enzyme systems have been obtained from Catharanthus roseus that mediate its formation from tryptamine and sec010ganin.’~ 4,2 1-Dehydrogeissoschizine is an intermediate75 in heteroyohimbine alkaloid biosynthesis.Geissoschizine (25) is into 19-epi-ajmalicine and (16R)- is~sitsirikine~~ by cell-free extracts of C. roseus. Tissue cultures which will carry out this biosynthesis have been from the same plant. Vindoline and catharanthine are precursors of the dimeric alkaloid A15(20’)-20‘-deoxyvinblastine which in turn is converted into ~inblastine.~~’~’ Strictosamide is the penultimate precursor of camptothecin.81 OT%H. H= \o .Glu aj-q (24) /N Me0,C (23) 66 P. M. Dewick and M. Martin Phytochemistry 1979,18,591 597 1309; 1980,19 2341. 67 K. Inoue Y. Shiobara H. Nayeshiro H. Inouye G. Wilson and M. H. Zenk J. Chem. SOC.,Chem. Commun.1979,957. 68 R. B. Herbert in ‘The Alkaloids’ ed. M. F. Grundon (Specialist Periodical Reports) The Chemical Society London 1979,vol. 9 p. 1. 69 E. Leete and M.-L. Yu Phytochemistry 1980 19 1093; E. Leete J. Chem. Soc. Chem. Commun. 1980 1170. 70 D. J. Robins and J. R. Sweeney J. Chem. Soc. Chem. Commun. 1979,120. 71 R. Cahill D. H. G. Crout M. B. Mitchell and U. S. Miller J. Chem. Soc. Chem. Commun. 1980,419. 72 R. B. Herbert and J. Mann J. Chem. Soc. Chem. Commun. 1980,841. ” N. Nagakura M. Ruffer and M.H. Zenk J. Chem. Soc. Perkin Trans. 1 1979 2308. 74 J. Stockigt Phytochemistry 1979,18 965. 75 M. Rueffer C. Kan-Fan H.-P. Husson J. Stockigt and M. H. Zenk J. Chem. Soc. Chem. Commun. 1979,1016. 76 J. Stockigt G. Hofle and A. Pfitzner Tetrahedron Lett.1980,21 1925. 77 S. L. Lee T. Hirata and A. I. Scott Tetrahedron Left. 1979 691; T. Hirata S. L. Lee and A. I. Scott J. Chem. Soc. Chem. Commun. 1979 1081. 78 A. I. Scott H. Mizukami T. Hirata and S. L. Lee Phytochemistry 198@,19,488. 79 R. L. Baxter C. A. Dorschel S. L. Lee and A. I. Scott J. Chem. Soc. Chem. Commun. 1979 257. F. Gueritte N. V. Bac Y. Langlois and P. Potier J. Chem. Soc. Chem. Commun. 1980,452. ” C.R.Hutchinson A. H. Heckendorf J. L. Straughn P. E. Daddona and D. E. Cane J. Am. Chem. Soc. 1979 101 3358. 296 J. R. Hanson N-Methylation precedes’’ the final cyclization in the construction of the tetracyc- lic ergoline ring system. The isoprenylation steps in echinulin biosynthesis have been showns3 to involve an inversion of configuration at the allylic pyrophosphate of isopentenyl pyrophosphate.During the biosynthesis of the neurotoxin roquefor- tine (26) the 3-pro-S hydrogen atom of histidine is removed in the formation of the dehydro-amino-acid moiety.84 Full papers have appeared on the biosynthesis of some Erythrina and benzylisoquinoline alkaloidss5 and on the Cephalotaxus a1 kaloids. s6 5 Porphyrin Biosynthesis Some aspects of the biosynthesis of the porphyrins have been the subject of controversy. Their biosynthesis has been the subject of a number of review^.^' Considerable use has been made of 13C n.m.r. techniques particularly those involv- ing the direct observation of biosynthetic intermediates in living cells in the n.m.r. tube and of 15N-13Ccoupling patterns.The stepwise binding of 6-aminolaevulinic acid in the formation of porphobilinogen has been examined,” whilst 13C n.m.r. experiments have shown that the order of assembly of the pyrrole rings in uro’gen I11 (30) is A -+D.89The biosynthesis of uro’gen I11 by the enzyme system deaminase:cosynthetase involves the head-to-tail assembly of the four porpho- bilinogen units (27) followed by intramolecular rearrangement. The function of deaminase is to assemble a linear bilane which in the absence of cosynthetase is released into the medium as a hydroxymethyl-bilane (28).90 The latter cyclizes ’’ H. Otsuka J. A. Anderson and H. G. Floss J. Chem. SOC., Chem. Commun. 1979,660. 83 J. K. Allen K. D. Barrow and A. J. Jones J. Chem. SOC.,Chem. Commun.1979 280. 84 K. D. Barrow P. W. Colley and D. E. Tribe J. Chem. SOC.,Chem. Commun. 1979,225; R. Vleggaar and P. L. Wessels ibid. 1980 160. D. S. Bhakuni S. Jain and R. Chaturvedi Tetrahedron 1979 35 2323; D. S. Bhakuni A. N. Singh and S. Jain ibid. 1980 36 2149; D. S. Bhakuni and S. Jain ibid. p. 2153; D. S. Bhakuni S. Jain and S. Gupta ibid. p. 2491; D. S. Bhakuni S. Jain and R. S. Singh ibid. p. 2525. 86 A. Gitterman R. J. Parry R. Dufresne D. D. Sternbach and M. D. Cabelli J. Am. Chem. SOC. 1980,102,2074; ” A. R. Battersby and E. McDonald Acc. Chem. Res. 1979,12 14. P. M. Jordan and J. S. Seehra J. Chem. SOC.,Chem. Commun. 1980,240. 89 A. R. Battersby C. J. R. Fookes G. W. J. Matcham E. McDonald and K. E. Gustafson-Potter J. Chem. SOC.,Chem. Commun.1979 316; A. R. Battersby C. J. R. Fookes G. W. J. Matcham and E. McDonald ibid. p. 539; A. R. Battersby C. J. R. Fookes E. McDonald and G. W. J. Matcham Bio-org. Chem. 1979,8,451. 90 A. I. Scott G. Burton and P. E. Fagerness J. Chem. SOC.,Chem. Commun. 1979 199; G. Burton P. E. Fagerness S. Hosozawa P. M. Jordan and A. I. Scott ibid. p. 202; P. M. Jordan G. Burton H. Nordlov M. M. Schneider L. Pryde and A. I. Scott ibid. p. 204; A. R. Battersby C. J. R. Fookes, K.E. Gustafson-Potter G. W. J. Matcham and E. McDonald ibid. p. 1155; A. R. Battersby R. G. Brereton C. J. R. Fookes E. McDonald and G. W. J. Matcham ibid. 1980 1124; A. I. Scott G. Burton P. M. Jordan H. Matsumoto P. E. Fagerness and L. M. Pryde ibid. p. 384; see also Can. J. Chem. 1980,58,1839.Biological Chemistry -Part (i) Biosynthesis chemically to uro’gen I (29) without rearrangement of ring D. In the presence of cosynthetase rearrangement occurs with the formation of uro’gen I11 (30). The decarboxylation of uro’gen I11 to coproporphyrinogen I11 takes place91 in a sequence starting with the acetic acid moiety on ring D and followed in a clockwise order by the acids on the rings A B and C. A series of methylated metabolites of uro’gen I11 have been detected92 as intermediates in the biosynthesis of vitamin BI2. The controversy which surrounded the structure of one of these 20-methylsirohydro- chlorin has now been Inthe ring-contraction of the trimethylisobacterio- chlorin to the corrin system of cobyrinic acid the C-20-methyl group is lost and not transferred to C-1.6 Other Metabolites derived from Amino-Acids The direct 13Cn.m.r. observation of the conversion of (L-a-amino-6-adipy1)-L- cysteinyl-D-valine (31)into isopenidin N (32) by a cell-free system derived from Cephalosporium acremonium has been reported.93 The biosynthesis of the epi- dithiodioxopiperazines such as gliotoxin has been reviewed.94 The reductive methylation of the sulphur bridge of gliotoxin has been reported.95 Feeding experi- ments with cyclo-(L-tyrosyl-L-serine)and phomamide (33) have led96 to a scheme for the formation of sirodesmin PL (34) in Phoma lingam. The unusual amino-acid 91 A. H. Jackson H. A. Sancovich and A. M. Ferramola de Sancovich Bioorg. Chem. 1980,9 71. 92 A. R. Battersby G. W. J.Matcham E. McDonald R. Neier M. Thompson W.-D. Woggon V. Y. Bykovsky and H. R. Morris J. Chem. Soc. Chem. Commun. 1979 185; N. G. Lewis R. Neier G. W. J. Matcham E. McDonald and A. R. Battersby ibid. p. 541; A. R. Battersby E. McDonald R. Neier and M. Thompson ibid. p. 960; G. Muller K. D. Gneuss H.-P. Kriemler A. I. Scott and A. J. Irwin J. Am. Chem. Soc. 1979 101,3655. 93 J. E. Baldwin B. L. Johnson J. J. Usher E. P. Abraham J. A. Huddleston and R. L. White J. Chem. Soc. Chem. Commun. 1980 1271. 94 G. W. Kirby Pure Appl. Chem. 1979,51,705. 95 G.W. Kirby D. J. Robins M. A. Sefton and R. R. Talekar J. Chem. Soc. Perkin Trans. 1 1980 119. 96 J.-P. Ferezou A. Quesnaeu-Thierry C. Servy E. Zissrnann and M. Barbier J. Chem. Soc. Perkin Trans. 1 1980 1739.298 J. R. Hanson HO 0YHNH (33) (34) (35) 3-amino-5-hydroxybenzoicacid initiates the formation of the polyketide chain in the ansamycin and maytansinoid group of antibiotics and is also an important precursor of porfiromycin (35).97 Reports have appeared on the biosynthesis of a number of Streptornyces antibio-tic~.~~ Streptolydigin is unusual for this group in that the polyketide portion contains propionate Malonomicin is a tetramic acid with an unusual amino-malonic acid moiety. It is derived"' from 2,3-diaminopropanoic acid acetate and succinate. The C-nucleoside antibiotic pyrazofurin contains a rare pyrazole ring which is derived'" from glutamic acid. Reports have appeared on the biosynthesis of spectinomycin,"* ~treptonigrin,''~ aplasrn~mycin,'~~ berninamy~in,''~ and indol- mycin.lo6 7 Miscellaneous Metabolites Using chirally labelled material it has been shown'" that the introduction of sulphur at C-4 into desthiobiotin proceeds with retention of configuration and with no loss of tritium from the adjacent position.In contrast the sulphur of lipoic acid which is introduced at C-4 of the parent octanoic acid is inserted with overall inversion of configuration.lo8 97 U. Hornemann J. H. Eggertand and D. P. Honer J. Chem. SOC.,Chem. Commun. 1980 11; J. J. Kibby I. A. McDonald and R. W. Rickards ibid. p. 768; M. G. Anderson J. J. Kibby R. W. Richards and J. M. Rothschild ibid.,p. 1277. 98 L. H. Hurley Acc. Chem. Res. 1980 13 263. 99 C. J. Pearce S. E. Ulrich and K.L. Rinehart J. Am. Chem. SOC.,1980,102,2510. loo D. Schipper J. L. van der Baan and F. Bickelhaupt J. Chem. SOC.,Perkin Trans. 1 1979,2017. J. G. Buchanan M. R. Hamblin G. R. 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