Enzyme catalysis inhibition

The theoretical description of electrocatalysis that takes into account electron and ion transfer and the transport process, the permeations of the substrates, and their combined involvement in the control over the overall kinetics has been elaborated by Albeiy and Hillman [312,313,373] and by Andrieux and Saveant [315], and a good summary can be found in [314]. Practically all of the possible cases have been considered, including Michaelis-Menten kinetics for enzyme catalysis. Inhibition, saturation, complex mediation, etc., have also been treated. The different situations have also been represented in diagrams. Based on the theoretical models, the respective forms of the Koutecky-Levich eqrration have been obtained, which make analyzing the resirlts of voltarrrmetry on stationary artd rotating disc electrodes a straightforward task. 

Elucidating Mechanisms for the Inhibition of Enzyme Catalysis An inhibitor interacts with an enzyme in a manner that decreases the enzyme s catalytic efficiency. Examples of inhibitors include some drugs and poisons. Irreversible inhibitors covalently bind to the enzyme s active site, producing a permanent loss in catalytic efficiency even when the inhibitor s concentration is decreased. Reversible inhibitors form noncovalent complexes with the enzyme, thereby causing a temporary de-... 

Nitrilases catalyze the synthetically important hydrolysis of nitriles with formation of the corresponding carboxylic acids [4]. Scientists at Diversa expanded the collection of nitrilases by metagenome panning [56]. Nevertheless, in numerous cases the usual limitations of enzyme catalysis become visible, including poor or only moderate enantioselectivity, limited activity (substrate acceptance), and/or product inhibition. Diversa also reported the first example of the directed evolution of an enantioselective nitrilase [20]. An additional limitation had to be overcome, which is sometimes ignored, when enzymes are used as catalysts in synthetic organic chemistry product inhibition and/or decreased enantioselectivity at high substrate concentrations [20]. 

Substances that do not target the active site but display inhibition by allosteric mechanisms are associated with a lower risk of unwanted interference with related cellular enzymes. Allosteric inhibition of the viral polymerase is employed in the case of HIV-1 nonnucleosidic RT inhibitors (NNRTl, see chapter by Zimmermann et al., this volume) bind outside the RT active site and act by blocking a conformational change of the enzyme essential for catalysis. A potential disadvantage of targeting regions distant from the active site is that these may be subject to a lower selective pressure for sequence conservation than the active site itself, which can lower the threshold for escape of the virus by mutation. 

Kurumbail RG, Kiefer JR, Mamett LJ. Cyclooxygenase enzymes catalysis and inhibition. Curr Opin Struct Biol 2001 11 752-60. 

Product inhibition and substrate inhibition are effects also known in enzyme catalysis that can reduce catalytic efficiency. Generally, catalytic systems (natural or artificial) based on covalent interactions are more sensitive towards inhibitions than non-covalent systems utilizing weak interactions Garcia-Junceda, E. (2008) Multi-Step Enzyme Catalysis, Wiley-VCH Verlag GmbH, Weinheim, Germany. 

Reversible Inhibition One common type of reversible inhibition is called competitive (Fig. 6-15a). A competitive inhibitor competes with the substrate for the active site of an enzyme. While the inhibitor (I) occupies the active site it prevents binding of the substrate to the enzyme. Many competitive inhibitors are compounds that resemble the substrate and combine with the enzyme to form an El complex, but without leading to catalysis. Even fleeting combinations of this type will reduce the efficiency of the enzyme. By taking into account the molecular geometry of inhibitors that resemble the substrate, we can reach conclusions about which parts of the normal substrate bind to the enzyme. Competitive inhibition can be analyzed quantitatively by steady-state kinetics. In the presence of a competitive inhibitor, the Michaelis-Menten equation (Eqn 6-9) becomes... 

We have already dealt with the subject of irreversible inhibitors under enzyme titration and location of the active site (Section 11.4.3.2). The phenomenon of reversible inhibition involves simple complexation of the inhibitor with the enzyme at a site which modifies the reactivity of the enzyme catalysis. 

A much more comprehensive and in-depth discussion of different types of inhibition can be found in Segel s book Enzyme Catalysis [61]. 

This article describes various approaches to inhibition of enzyme catalysis. Reversible inhibition includes competitive, uncompetitive, mixed inhibition, noncompetitive inhibition, transition state, and slow tight-binding inhibition. Irreversible inhibition approaches include affinity labeling and mechanism-based enzyme inhibition. The kinetics of the various inhibition approaches are summarized, and examples of each type of Inhibition are presented. 

Enzyme Inhibition, Mechanisms of Enzyme Inhibition, Tools to Study Enzyme Kinetics, Techniques to Study Kinetic Isotope Effects Enzyme Catalysis, Chemistry of... 

The zeolite is rigid and ordered, and lacks conformational adaptability, in contrast to an enzyme, which can coil, uncoil, and twist around. Yet the zeolite can incorporate transition metal functions—these are of prime importance in enzyme catalysis—and it can effect redox reactions reactions over zeolites can be inhibited by competitive adsorption of reactants, products, solvents, or poisons—a phenomenon observed in biological and some other inorganic heterogeneous catalytic systems Rideal kinetics have been identified in some zeolite-catalyzed alkylations, a pattern which has its parallels in the enzyme field a few cases of stereospecificity (such as orfho-alkylation effects, unusual olefin isomer ratios), where a transition state not otherwise attainable intervenes, may exist. What better group of catalysts than zeolites might there have been to activate the evolutionary process in the dark, fermenting Pre-Cambrian seas some 1,000,000,000 years ago ... 

AMP is a competitive inhibitor (see "Enzymes Catalysis and Kinetics" Lecture) of Adenylosuccinate Synthetase, GMP competitively inhibits IMP Dehydrogenase. Note GTP is required for AMP syndesis and ATP is required for GMP synthesis, hence there is coordinated regulation of these nucleotides. 

Since biological systems are dynamic, with many different processes taking place and many different substances present, buffers are necessary to prevent the kind of wide variation of pH that can inhibit proper enzyme catalysis. Thus, a proper pH aids in regulating the reaction rates associated with certain enzymes and maintaining them at levels appropriate for their particular functions. Two important biological buffers are the phosphate buffer system that regulates pH for the fluid inside cells and the carbonic acid buffer system that regulates pH for blood plasma. The chemical equations for these buffers are shown below for an aqueous solution. 

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