Inhibitor Mechanisms

Morisseau C, Hammock BD. Epoxide hydrolases mechanisms, inhibitor designs, and biological roles. Annu Rev Pharmacol Toxicol 2005 45 311-333. 

Irreversible inhibition with based-mechanism inhibitors (suicide-substrates)... 

This book is one of the best known overall testaments of enzyme chemistry. It covers measurements, preparation, kinetics, nomenclature, specificity, mechanisms, inhibitors, cofactors, structures, biosynthesis, enzyme systems, and enzyme biology. In addition, a fairly broad list of classified enzymes and crystallized enzymes is appendicized. The book... 

The most thoroughly studied mechanism of protein protease inhibitors is that of the standard mechanism (or Canonical or Laskowski mechanism) inhibitors of serine proteases (1) (Fig. 2). Standard mechanism inhibitors include the Kazal, Kunitz, and Bowman-Birk family of inhibitors and bind in a lock-and-key fashion. Ah standard mechanism inhibitors insert a reactive loop into the active site of the protease, which is complementary to the substrate specificity of the target protease and binds in an extended fi-sheet with the enzyme in a substrate-like manner. WhUe bound to the protease, the scissile bond of standard mechaiusm inhibitors is hydrolyzed very slowly, but products are not released and the amide bond is re-ligated. The standard mechanism is an efficient way to inhibit serine proteases, and it is thus used by many structurally... 

Standard mechanism inhibitors are classified strictly as inhibitors of serine proteases. There have been reports of inhibitors of other classes of proteases that have similar mechanisms to those of standard mechanism inhibitors, though. Initial studies on the streptomyces metalloprotease inhibitor (SMPl) suggest that it inhibits the metalloprotease thermolysin through a substrate-like binding mechanism (2). Similarly, staphostatin B, a cysteine protease inhibitor from Staphylococcus aureus, binds in a substrate-like manner in the active site of staphopain cysteine proteases. However, staphostatin B has a glycine PI residue, which adopts a backbone conformation that seems to prevent nucleophilic attack of the scissiie bond (3). 

In contrast to the protein inhibitors which act by the standard mechanism of proteinase inhibition [52a], a,-PI reacts only weakly with anhydrochymotrypsin [57] and not at all with anhydrotrypsin [58]. Also, unlike I (the product of the standard mechanism inhibitors), a,-PI (otj-PI which has been cleaved) is not a proteinase inhibitor. 

Mechanism inhibitor with B with B (Figure) with A with A (Figure)... 

Mechanisms of Action.—Reviews on enzyme mechanisms have been published, and one of them includes diagrams of the chemistry that occurs at the active sites. A book on enzyme kinetics includes sections on one-substrate, linear, and branching mechanisms, inhibitors, activators, co-operative interactions, and isotopic exchange. ... 

Alkyl and peroxyl radicals alternating lead the chain process. Therefore, oxidation can be retarded by acceptors of both alkyl and peroxyl radicals. Autooxidation develops as a self-initiated ROOH forming chain reaction. Hence, autooxidation can be retarded by the decomposition of hydroperoxide or decreasing the rate of its decomposition to radicals. According to the corrqrlicated oxidation mechanism, inhibitors in mechanism of their action can be divided into the following six groups. 

Gefflaut, T., Blonski, C., Perie, J., and Willson, M., Class I aldolases Substrate specificity, mechanism, inhibitors and structural aspects. Prog. Biophys. Mol. Biol. 1995,63 (3), 301-340. 

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