Enzyme-Substrate Enzyme-Inhibitor Interactions

2018 ◽  
pp. 181-197
Author(s):  
J. P. Glusker
Keyword(s):  
Enzyme Inhibitor ◽  
Enzyme Substrate

scholarly journals Intracellular enzymes of collagen biosynthesis in human platelets

Blood ◽  
1977 ◽  
Vol 50 (1) ◽  
pp. 29-37
Author(s):  
H Anttinen ◽  
L Tuderman ◽  
A Oikarinen ◽  
KI Kivirikko
Keyword(s):  
Enzyme Inhibitor ◽  
Relative Activity ◽  
Human Platelets ◽  
Prolyl Hydroxylase ◽  
Skin Extract ◽  
Collagen Biosynthesis ◽  
Substrate Complex ◽  
Enzyme Substrate ◽  
Intracellular Enzymes ◽  
Native Collagen

Activities of four intracellular enzymes of collagen biosynthesis-- prolyl hydroxylase, lysyl hydroxylase, collagen galactosyltransferase, and collagen glucosyltransferase--were demonstrated in human platelets, and the presence of prolyl hydroxylase protein was further demonstrated by direct radioimmunoassay. The ratio of the specific activities of the four enzymes in the four enzymes in the human platelet extract to those in human adult skin extract varied from about 0.1 to 1, the lowest relative activity being found with prolyl hydroxylase and the highest with collagen glucosyltransferase. Only a very small amount of prolyl hydroxylase protein, probably 1%, was in the form of the active enzyme tetramer. The collagen glucosyltransferase from human platelets readily glucosylated galactosylhydroxylysine in denatured collagen, but did not glucosylate native collagen. Also, native collagen did not act as an inhibitor of the glucosylation reaction. Therefore, platelet collagen glucosyltransferase cannot form either an enzyme--substrate complex or an enzyme--inhibitor complex with native collagen. The results thus argue against the theory which maintains that platelet collagen glucosyltransferase is involved in collagen--platelet adhesion.

scholarly journals 5-Substituted N-(9H-purin-6-yl)-1,2-oxazole-3-carboxamides as xanthine oxidase inhibitors

2020 ◽  
Vol 15 (1) ◽  
pp. 20-25
Author(s):  
Oksana Muzychka ◽  
Olexandr Kobzar ◽  
Oleg Shablykin ◽  
Volodymyr Brovarets ◽  
Andriy Vovk
Keyword(s):  
Xanthine Oxidase ◽  
Inhibition Efficiency ◽  
Enzyme Inhibitor ◽  
Oxazole Ring ◽  
Inhibitor Complex ◽  
Enzyme Substrate ◽  
Xanthine Oxidase Inhibitors ◽  
Ic50 Values ◽  
Nanomolar Range

Synthetic 6-substituted purine derivatives are known to exhibit diverse bioactivity. In this paper, a series of N-(9H-purin-6-yl)-1,2-oxazole-3-carboxamide derivatives were synthesized and evaluated in vitro against xanthine oxidase, an enzyme of purine catabolism. The introduction of aryl substituent at position 5 of the oxazole ring was found to increase the inhibition efficiency. Some of the inhibitors containing 5-substituted isoxazole and purine moieties were characterized by IC50 values in the nanomolar range. According to the kinetic data, the most active N-(9H-purin-6-yl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-oxazole-3-carboxamide demonstrated a competitive type of inhibition with respect to the enzyme-substrate. Molecular docking was carried out to elucidate the mechanism of enzyme-inhibitor complex formation. The data obtained indicate that xanthine oxidase may be one of the possible targets for the bioactive purine carboxamides.

Enzyme substrate and inhibitor interactions

1975 ◽  
Vol 272 (915) ◽  
pp. 87-97 ◽  
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Catalytic Mechanism ◽  
Tertiary Structure ◽  
Enzyme Inhibitor ◽  
High Specificity ◽  
Intermediate Stage ◽  
Enzyme Substrate ◽  
Consequent Reduction ◽  
Simple Interaction

An enzyme is designed to bind most tightly to a substrate when it is in the transition state of the reaction which the enzyme catalyses. The consequent reduction of the activation energy of the reaction constitutes the catalytic mechanism. The energetic contributions of different features of the interaction can only be crudely assessed, but they are dominated by entropically driven effects. The binding site of trypsin orients the substrate so that the reacting groups are correctly placed for reaction to occur. Apart from two side chains which take part in chemical steps of the reaction, the enzyme behaves almost as a rigid body. The full binding interactions are only developed when the substrate is in an intermediate stage of the reaction. The tightly bound complexes of trypsin with protein trypsin inhibitors have proved amenable to structural analysis. Enzyme inhibitor interactions, which account for almost 80 kJ mol -1 of interaction energy, are known fairly accurately. The similarity of the two known trypsin inhibitor structures, close to the primary binding site, indicates a high specificity, even for this simple interaction. In cases where no large conformational changes occur the specificity of an enzyme should be predictable from accurate knowledge of its tertiary structure.

scholarly journals The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2

2007 ◽  
Vol 401 (3) ◽  
pp. 645-650 ◽  
Author(s):  
Anne Mølgaard ◽  
Jose Arnau ◽  
Conni Lauritzen ◽  
Sine Larsen ◽  
Gitte Petersen ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Enzyme Inhibitor ◽  
Complex Structure ◽  
Dipeptidyl Peptidase ◽  
Cathepsin G ◽  
Native Enzyme ◽  
Zymogen Activation ◽  
Inhibitor Complex ◽  
Enzyme Substrate ◽  
Lysosomal Cysteine Protease

hDDPI (human dipeptidyl peptidase I) is a lysosomal cysteine protease involved in zymogen activation of granule-associated proteases, including granzymes A and B from cytotoxic T-lymphocytes and natural killer cells, cathepsin G and neutrophil elastase, and mast cell tryptase and chymase. In the present paper, we provide the first crystal structure of an hDPPI–inhibitor complex. The inhibitor Gly-Phe-CHN2 (Gly-Phe-diazomethane) was co-crystallized with hDPPI and the structure was determined at 2.0 Å (1 Å=0.1 nm) resolution. The structure of the native enzyme was also determined to 2.05 Å resolution to resolve apparent discrepancies between the complex structure and the previously published structure of the native enzyme. The new structure of the native enzyme is, within the experimental error, identical with the structure of the enzyme–inhibitor complex presented here. The inhibitor interacts with three subunits of hDPPI, and is covalently bound to Cys234 at the active site. The interaction between the totally conserved Asp1 of hDPPI and the ammonium group of the inhibitor forms an essential interaction that mimics enzyme–substrate interactions. The structure of the inhibitor complex provides an explanation of the substrate specificity of hDPPI, and gives a background for the design of new inhibitors.

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