Enzymes: Irreversible Inhibition

Abstract

Abstract Many drugs that are in clinical use work by irreversibly inhibiting specific enzymes, either in the individual being treated or in an invading organism. Enzyme inhibitors are also of value for understanding the behaviour of individual enzymes and metabolic systems. Recovery from irreversible inhibition requires the synthesis of new enzyme. Although those irreversible inhibitors that react with specific groups in the enzyme protein generally inhibit more than one enzyme, those that initially form a noncovalent complex with the enzyme, with subsequent reaction within that complex leading to the formation of a covalent bond, can show a high degree of selectivity. Kinetic studies, which are detailed in this account, can be used to distinguish the different types of inhibition and the factors that contribute to effectiveness and selectivity. Key Concepts Irreversible inhibition cannot be reversed by the removal of the excess inhibitor from the system. Recovery from reversible inhibition depends on the removal of the inhibitor from the system, whereas recovery from irreversible inhibition requires the synthesis of fresh enzyme. Enzyme turnover in the tissues is a balance between the rate of its synthesis and degradation. Nonspecific irreversible inhibitors can react with several groups of the same type in different proteins. Specific irreversible inhibitors form an initial noncovalent complex with the enzyme before the reaction within that complex to form a covalent bond. Active‐site‐directed inhibitors contain a reactive grouping attached to a substrate analogue. Mechanism‐based inhibitors can be highly specific because they depend on the activity of the enzyme to form a reactive intermediate that then reacts irreversibly with the enzyme. Suicide substrates behave as both substrates and irreversible enzyme inhibitors in divergent processes. Dosage schedule for effective therapy with irreversible inhibitors is dependent on the half‐life of enzyme turnover.