In biochemistry, suicide inhibition, also known as suicide inactivation or mechanism-based inhibition, is an irreversible form of enzyme inhibition that occurs when an enzyme binds a substrate 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 a prosthetic group or a coenzyme, forming electrophilic alpha and beta unsaturated carbonyl compounds and imines.
Clavulanic acid, which inhibits β-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 as parathion are organophosphorus suicide inhibitors of acetylcholinesterase with aging times dependent on the lability of leaving groups present on the organophosphorus moiety of the molecule.[1]
5-fluorouracil acts as a suicide inhibitor of thymidylate synthase during the synthesis of thymine from uridine. This reaction is crucial for the proliferation of cells, particularly those that are rapidly proliferating (such as fast-growing death cancer tumors). By inhibiting this step, cells die from a thymineless death because they have no thymine to create more DNA. This is often used in combination with methotrexate, a potent inhibitor of dihydrofolate reductase enzyme.
Suicide inhibitors are used in what is called "rational drug 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 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. doi:10.1016/j.tox.2006.04.030. PMID 16720069.
^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. PMID 874623.
^Johnson DS, Weerapana E, Cravatt BF (June 2010). "Strategies for discovering and derisking covalent, irreversible enzyme inhibitors". Future Medicinal Chemistry. 2 (6): 949–64. doi:10.4155/fmc.10.21. PMC2904065. PMID 20640225.
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suicide, inhibition, prevention, suicide, suicide, prevention, biochemistry, suicide, inhibition, also, known, suicide, inactivation, mechanism, based, inhibition, irreversible, form, enzyme, inhibition, that, occurs, when, enzyme, binds, substrate, analog, fo. For prevention of suicide see Suicide prevention In biochemistry suicide inhibition also known as suicide inactivation or mechanism based inhibition is an irreversible form of enzyme inhibition that occurs when an enzyme binds a substrate 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 a prosthetic group or a coenzyme forming electrophilic alpha and beta unsaturated carbonyl compounds and imines Stereoisomers of Soman a G series nerve agent and suicide inhibitor of acetylcholinesterase Note the non carbon chiral center Contents 1 Examples 2 Rational drug design 3 See also 4 ReferencesExamples editSome clinical examples of suicide inhibitors include Disulfiram which inhibits the acetaldehyde dehydrogenase enzyme Aspirin which inhibits cyclooxygenase 1 and 2 enzymes Clavulanic acid which inhibits b lactamase clavulanic acid covalently bonds to a serine residue in the active site of the b 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 b lactamase Penicillin which inhibits DD transpeptidase from building bacterial cell walls Sulbactam which prohibits penicillin resistant strains of bacteria from metabolizing penicillin AZT zidovudine and other chain terminating nucleoside analogues used to inhibit HIV 1 reverse transcriptase in the treatment of HIV AIDS Eflornithine one of the drugs used to treat sleeping sickness is a suicide inhibitor of ornithine decarboxylase Nerve agent and related pesticides such as parathion are organophosphorus suicide inhibitors of acetylcholinesterase with aging times dependent on the lability of leaving groups present on the organophosphorus moiety of the molecule 1 5 fluorouracil acts as a suicide inhibitor of thymidylate synthase during the synthesis of thymine from uridine This reaction is crucial for the proliferation of cells particularly those that are rapidly proliferating such as fast growing death cancer tumors By inhibiting this step cells die from a thymineless death because they have no thymine to create more DNA This is often used in combination with methotrexate a potent inhibitor of dihydrofolate reductase enzyme O6 Benzylguanine a drug which depletes O6 alkylguanine DNA alkyltransferase by virtue of its similarity to the DNA repair protein s target lesion Exemestane a drug used in the treatment of breast cancer is an inhibitor of the aromatase enzyme Selegiline 2 although in the attached reference the compound is called a suicide inactivator not inhibitor Vigabatrin an anticonvulsant is a suicide inhibitor of GABA T Rational drug design editSuicide inhibitors are used in what is called rational drug 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 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 See also editMetabolic trappingReferences edit 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 doi 10 1016 j tox 2006 04 030 PMID 16720069 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 PMID 874623 Johnson DS Weerapana E Cravatt BF June 2010 Strategies for discovering and derisking covalent irreversible enzyme inhibitors Future Medicinal Chemistry 2 6 949 64 doi 10 4155 fmc 10 21 PMC 2904065 PMID 20640225 nbsp This enzyme related article is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title Suicide inhibition amp oldid 1185090258, wikipedia, wiki, book, books, library,
