Suicide inhibition, also known as suicide inactivation and mechanism-based inactivation, is a form of irreversible enzyme inhibition that occurs when an enzyme binds a substrate analogue and forms a complex with it during the "normal" catalysis reaction.
The catalytic step will generate one of three reactive groups on the substrate analogue that will allow for the irreversible inhibition: an α- or β-haloketone, a βγ unsaturated carbon, or a βγ acetylenic carbon.
Some clinical applications of suicide inhibitors include:
- Penicillin, which inhibits transpeptidase from building bacterial cell walls.
- Sulbactam, which prohibits penicillin-resistant strains of bacteria from metabolizing penicillin.
- Allopurinol, which inhibits uric acid production by xanthine oxidase in the treatment of gout.
- AZT (zidovudine) and other chain-terminating nucleoside analogues used to inhibit HIV-1 reverse transcriptase in the treatment of HIV/AIDS.
Rational drug design
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 offering very few side effects.
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