Enzyme-catalysed covalent inhibition

To help clarify the effect of inhibitors, it is useful to divide inhibition into four classes reversible, allosteric, irreversible covalent, enzyme-catalysed covalent. 

In addition to substrate concentration, two groups of compounds alter the rate of an enzymic reaction by specific mechanisms. Activators are compounds which combine with an enzyme or enzyme-substrate complex to effect an increase in activity without being modified by the enzyme. Inhibitors are compounds which decrease the rate of an enzyme-catalysed reaction. Inhibitors are divided into two categories irreversible and reversible inhibitors. Irreversible inhibition involves the covalent bonding of the inhibitor to a functional group at the active site or elsewhere on the enzyme. Because the effective concentration of the enzyme is progressively declining, irreversible inhibition cannot be analysed by Michaelis-Menten kinetics. 

Many clinically important yff-lactamases are serine proteases that catalyse y5-lactam hydrolysis by a double displacement mechanism involving a covalent acyl-enzyme intermediate. Inhibitors of these enzymes exert their effect by the formation of a stable acyl-enzyme complex. In most cases, this is as a result of changes that take place in the acyl residue after interaction with the enzyme, that is, the inhibitors are mechanism-based. In other cases, the inhibition of yS-lactamases may merely be due to the formation of a relatively stable covalent acyl-enzyme complex without additional alteration [31]. 

In vitro and in vivo data indicate that the antithyroidal activity of resorcinol is caused by inhibition of thyroid peroxidase enzymes, resulting in decreased thyroid hormone production and increased proliferation due to an increase in the secretion of TSH (see section 8.8). The iodination process is catalysed by a haemcontaining enzyme. Resorcinol is known to form covalent bonds with haem (Sessler et al., 1988). 

This inhibitory effect can be reversible or irreversible. In the irreversible case the inhibitor, which is a poison in this instance, binds strongly to the enzyme, usually via covalent bonds. In the reversible case the inhibitor can be removed from the complex (Smith, 2010). Varions forms of reversible inhibition have been investigated and classified based on the catalyse step at which they interact. Generally, when inhibitors bind to the enzyme, the magnitnde decreases. If they bind to the enzyme complex, the decreases. 

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