Inbiochemistry,suicide inhibition, also known assuicide inactivation ormechanism-based inhibition, is an irreversible form ofenzyme inhibition that occurs when anenzyme binds asubstrate analog and forms an irreversible complex with it through a covalent bond during the normal catalysis reaction. The inhibitor binds to the active site where it is modified by the enzyme to produce a reactive group that reacts irreversibly to form a stable inhibitor-enzyme complex. This usually uses aprosthetic group or acoenzyme, forming electrophilic alpha and beta unsaturatedcarbonyl compounds andimines.
Clavulanic acid, which inhibitsβ-lactamase: clavulanic acid covalently bonds to a serine residue in the active site of the β-lactamase, restructuring the clavulanic acid molecule, creating a much more reactive species that attacks another amino acid in the active site, permanently inactivating it, and thus inactivating the enzyme β-lactamase.
Nerve agent and related pesticides such asparathion are organophosphorus suicide inhibitors ofacetylcholinesterase with aging times dependent on thelability of leaving groups present on the organophosphorus moiety of the molecule.[1]
5-fluorouracil acts as a suicide inhibitor ofthymidylate synthase during the synthesis ofthymine fromuridine. This reaction is crucial for the proliferation of cells, particularly those that are rapidly proliferating (such as fast-growing cancer tumors). By inhibiting this step, cells die from athymineless death because they have no thymine to create more DNA. This is often used in combination withmethotrexate, a potent inhibitor ofdihydrofolate reductase enzyme.
Suicide inhibitors are used in what is called "rationaldrug design" where the aim is to create a novel substrate, based on already known mechanisms and substrates. The main goal of this approach is to create substrates that are unreactive until they are within that enzyme's active site and at the same time being highly specific. Drugs based on this approach have the advantage of very few resulting side effects.[3]
^Aurbek N, Thiermann H, Szinicz L, Eyer P, Worek F (July 2006). "Analysis of inhibition, reactivation and aging kinetics of highly toxic organophosphorus compounds with human and pig acetylcholinesterase".Toxicology.224 (1–2):91–9.Bibcode:2006Toxgy.224...91A.doi:10.1016/j.tox.2006.04.030.PMID16720069.
^Fowler JS (July 1977). "2-Methyl-3-butyn-2-ol as an acetylene precursor in the Mannich reaction. A new synthesis of suicide inactivators of monoamine oxidase".The Journal of Organic Chemistry.42 (15):2637–7.doi:10.1021/jo00435a026.PMID874623.
