Enzymes: Irreversible Inhibition

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 dependant on the half‐life of enzyme turnover.

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

“…We addressed this inconsistency by specifically assessing the ␤-glucosidase activity of GBA2 for its sensitivity to inhibition by CBE, using membrane preparations that are devoid of GBA. We found that GBA2 is inactivated by CBE, in a time-dependent fashion, which is typical for mechanism-based enzyme inhibitors (80,81). Measurement of K I and k inact values showed that CBE bound GBA2 with less affinity and that CBE inactivated GBA2 at a lower rate, as compared with the interaction of CBE and GBA.…”

Parameters for Irreversible Inactivation of Monoamine Oxidase

“…Other propargylamine inactivators similarly form adducts at N5 of the FAD, including clorgyline [ 16 ], selegiline [ 16 ] and rasagiline [ 17 ], and two compounds examined in this work, ASS234 [ 18 ] and F2MPA [ 19 ]. Formation of the adducts can be measured as the time-dependent onset of inhibition not reversed by dialysis [ 20 ] and directly observed by changes in the spectrum of the FAD cofactor [ 11 , 18 ]. The irreversible inhibition by these compounds involves activation by MAO to give an allenyl imine product that reacts chemically to form a covalent bond to the flavin prosthetic group [ 11 , 21 , 22 , 23 ].…”

Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge

“…(ii) Irreversible inhibitors that irreversibly binds the protein. In this case, the recovery of enzymatic functions does occur with the physiological turn-over [89], and their ability to closely tie their target results in a prolonged therapeutic response with a consequent decrease in doses and frequency of administration, and a significantly increased patient compliance [90]. Obviously, they also have disadvantages, such as episodes of toxicity and hypersensitivity [87,91].…”