Suicide inhibition

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 analogue 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.

Examples

Some clinical examples of suicide inhibitors include:

• Aspirin, which inhibits cyclooxygenase 1 and 2 enzymes.
• Penicillin, which inhibits DD-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.
• Eflornithine, one of the drugs used to treat sleeping sickness, is a suicide inhibitor of ornithine decarboxylase.
• Sarin is a suicide inhibitor of acetylcholinesterase.
• 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 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.
• Exemestane, a drug used in the treatment of breast cancer, is an inhibitor of the aromatase enzyme.
• Selegiline,^[1] 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

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.

See also

• Metabolic trapping

References

1. Fowler, Joanna S. (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.