摘要:

AbstractThe proceedings of a symposium on current trends in enzyme‐guided biomedical research and its relation to potential new drug discovery are reviewed. Topics under discussion include current concepts in enzyme inhibition, the mechanism and inhibition of phopholipase A2, 5‐lipoxygenase and inflammation, the protease/antiprotease hypothesis of emphysema, carbonic anhydrase and glaucoma, GTP‐binding proteins and adenylate cyclase, and the calpain hypothesis of memory st

ISSN:0272-4391    

DOI:10.1002/ddr.430100402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractA large number of surface membrane receptors are coupled to proteins (N or G) that bind GTP. The N proteins generally consist of three distinct subunits, designated α, β, and γ, of which only the α‐subunit binds and degrades GTP to GDP. The α subunits are homologous in structure at the GTP‐binding domains but vary in function. When activated by GTP‐γ‐S and Mg ions or by homones and GTP, α‐subunits are released from the complexes with the β/γ‐subunits remain membrane‐bound during the activation of the α‐subunits. The α‐subunits regulate adenylate cyclase; activate phospholipases that break down phosphoinositides to inositol‐trisphosphate and diacylglycerides; regulate potassium channels and voltage‐activated calcium channels; and may regulate Mg ion channels and glucose transport. Based on the varied actions of the same α‐subunit and evidence that the α‐subunits are modified by kinases and possibly other protein‐modifying enzymes, it is proposed that these GTP‐binding proteins are the primary messengers of hormone action; when released from their moorings with β/γ‐complexes (and receptors) into the cytosol the α‐proteins are suggested to regulate several signal‐amplifying processes (enzymes, channels, transporters) and are subject to alterations in structure and function. In this sense the α‐GTP‐binding

ISSN:0272-4391    

DOI:10.1002/ddr.430100403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThe role of phospholipases in cellular activation and arachidonic acid production for prostaglandin and leukotriene biosynthesis is reviewed. Particular emphasis is placed on the function of phospholipase A2in the processes. The experimental basis of our current state of knowledge of the mechanism of action of the pure, extracellular phospholipase A2is considered in detail. Experimental approaches dealing with lipid activation, surface dilution kinetics, and enzyme aggregation are considered, and the “dual phospholipid model” for phospholipase A2action at the lipid/water interface is described in detail. The kinetic analysis of phospholipase A2inhibitors, includingp‐bromophenacylbromide, manoalide, and an alkylether amide analogue of phosphatidylcholine, is considered in light of this

ISSN:0272-4391    

DOI:10.1002/ddr.430100404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractCompactin and related compounds are highly effective inhibitors of HMG‐CoA (Hydroxymethylglutaryl‐CoA) reductase. These compounds consist of two major structural components: (1) a component resembling hydroxymethyl glutarate and (2) a hydrophobic region. It is concluded that the hydroxymethyl glutarate moiety of these inhibitors interacts with the hydroxymethyl glutarate‐binding domain of the active site. It is postulated that the hydrophobic moiety of these inhibitors interacts with a hydrophobic area of the enzyme that is not part of the active site. Strong binding is the consequence of this two‐point interation. Peptidyl tri‐fluoroketones are effective inhibitors of chymotrypsin and elastase and are probably transition‐state analogs. These inhibitors form an adduct with the activesite serine as determined by X‐ray crystallography and nuclear magnetic resonance spectroscopy. Maximum inhibition is obtained if inhibitors interact with the S and S′ binding domains. The structure of ovomucoids, protein inhibitors of serine proteases, serves as a good model for the determination of the amino acid sequence to be used in that portion of the inhibitor which interacts with the S′ domain. The best amino‐acid sequence to be used in that area of the inhibitor which interacts with the S‐binding domain corresponds to the amino‐acid sequence found in substrat

ISSN:0272-4391    

DOI:10.1002/ddr.430100405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThe hypothesis that emphysema might be caused by an imbalance between proteases and antiproteases in the lungs arose shortly after the discovery of the premature and familial occurrence of emphysema in persons with homozygous alpha‐1‐protease inhibitor deficiency. Experimental evidence for support of this hypothesis has come from experimental induction of emphysema in animals by proteases. The ability of proteases to induce emphysema is proportional to their elastolytic potency. The importance of elastin degradation as a cause of the development of emphysema has also come from experiments of genetic models in which elastin crosslinking is prevented. The neutrophilis believed to be the most likely source of elastase in the induction of the emphysema of smokers. Alpha‐1‐protease inhibitor is the most important antiprotease. Alpha‐1‐antiprotease is susceptible to oxidative inactivation by cigarette smoke or by endogenous oxidants. Oxidants from cigarette smoke may also interfere with proper elastin repair. Serine proteases have also been shown to produce secretory cell metaplasia in the central intrapulmonary bronchi of hamsters. The discovery of secretory leukoprotease inhibitor in sputum and its production by bronchial secretory cells raises the possibility that secretory cell metaplasia in humans may also be caused by an imbalance between proteases and antiproteases. Although evidence for the validity of the proteaselantiprotease hypothesis of the phogenesis of emphysema and chronic bronchitis in human smokers is still indirect, the development of supplemental antiprotease therapy seems rational for the prevention of progression of these diseases in persons who are unable to s

ISSN:0272-4391    

DOI:10.1002/ddr.430100406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThe chemistry and physiology of carbonic anhydrase are reviewed in relation to pharmacological progress in the development of sulfonamide inhibitors. The major organ systems are briefly dicussed. From the medical point of view, the major thrust is now for the treatment of glaucoma. The physiology of aqueous humor formation with respect to ion transport is discussed, and it is shown that a key event is the catalytic formation of HCO3−from CO2and OH−. The newly formed HCO3−is linked to NA+and fluid movement to produce aqueous humor. Inhibition of HCO3−sunthesis sulfonamides reduces aqueous formation and lowers pressure in normals and in glucoma.Four sulfonamides have been used sytemically, the chief being acetazolamide. None of these works topically; they do not reach the ciliary process in adequate concetrations. New programs have begun, searching for sulfonamides of different properties that cross the cornea in effective concetrations to inhibit carbonic anhydrase in the ciliary porcess. The key to the problems seems to be to search for a balance between water and lipid solubility, maintaining high activity against the enzyme. This has been achieved, and new structures described from this and other laboratories lower pressure in the rabbit nearly as well as systemic sulfonamides.Corneal permeabilities to test compounds (in vitro) in rabbit and man are similar, but accession to the auqeous (in vivo) is less in man. This may make the goal difficult, and the reasons for this difference are being e

ISSN:0272-4391    

DOI:10.1002/ddr.430100407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

Abstract5‐Lipoxygenses are enzymes in leukocytes and mast cells that oxidize arachidonic acid to 5‐hydroperoxyeicosatetraenoic acid, which is in turn converted to a variety of products including leukotriene B4and the sulfidoleukotrienes (LTC4, LTD4and LTE4). These substances exert a broad range of biologic actions including effects on cell migration, enzyme secretion, smooth muscle contraction in the respiratory and gastrointestinal tracts, and vascular permeability. Considerable evidence now implicates these products in a variety of acute and chronic inflammatory responses in vivo as well as in acute allergic reactions affecting the airway and s

ISSN:0272-4391    

DOI:10.1002/ddr.430100408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractConsiderable progress has been made in the analysis of learning and memory both at the level of the chemical processes involved in translating brief phusiological events into long‐lasting changes in synaptic efficacy and at the level of the location of the changes responsible of behavioral phenomenon of memory. This review focuses primarily on recent findings concerning the phenomenon of long‐term potentiation (LTP) of synaptic transmission elicited in hippocampal pathways by certain patterns patterns of electrial stimulation of various pathways. We first discuss the nature of the physiological events which are critically involved in LTP induction and indicate that these events are linked with naturally occurring patterns of activity in behaving animals. Detailed analysis of the physiological events taking place in the initial period of LTP induction points out a very specific sequence of biochemical/biophysical mechanisms that play a critical role in triggering LTP. We then briefly review the evidence indicting that LTP induction is accompanied by various types of structural modifications that have been proposed to be responsible for the long duration of the synaptic changes. This is followed by the description of a candidate biochemical mechanism that links the initial events triggered by LTP‐inducing stimulations and the long‐lasting modifications in synaptic structure and function. The final section presents our efforts to situate the analysis of the LTP phenomenon in the broader context of learning and memory and in particular indicates how the knowledge obtained at the biochemical and cellular level can be used to design new strategies for a pharmacological analysis of the memory pr

ISSN:0272-4391    

DOI:10.1002/ddr.430100409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430100410

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430100401

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY