Suicide inhibition

Suicide inhibition, also known as suicide inactivation, is a form of irreversible 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.

Examples

Some clinical examples 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.
• Eflornithine, one of the drugs used to treat sleeping sickness is a suicide inhibitor of ornithine decarboxylase.
• 5-fluourouracil acts as a suicide inhibitor of thymidlyate 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 "thymine-less" 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.

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.