Question

How does a suicide inhibitor and transition state analogues work on an enzyme? Could they be used in developing pharmaceuticals?

Answer 1

suicide 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 catalgtiv reaction.

These are inert molecule that is transformed by an enzyme at its active site and become a new reactive compound ,which inactivated the enzyme irreversibly.

This new reactive compound is the transition state analogue (resembles the subsrate).The inhibitor is nonreactive until they bind to the active site of the enzyme.


At the enzyme active site these inhibitors form a permanent complex via formation of covalent bonds with certain amino acids in the active site of the enzyme.Consequently, they cannot be displaced by the addition of excess substrate
Therefore, they are irreversible, non-competitive enzyme inhibitors.

enzyme treats the inhibitor as if it is a
normal substrate.

Reaction with the suicide inhibitor removes the active enzyme to which it is binded.For this reason the inhibitor is known as suicide inhibitor.

There are many drugs made from suicide inhibitors.Some examples are:

▪Aspirin,inhibit Cyclo-oxygenase 1 and 2
▪Penicillin,inhibit DD-traspeptidase
▪5 fluorouracil ,inhibitor of Thymidylate synthase
▪Allopurinol,inhibit Xanthin oxidase (anti gout drug)
▪Exemestane,inhibits Aromatase enzyme (treating breast cancer)

Deigning of drugs that accurately resembles transition state analogue is challenging because of the unstable,poorly characterised structure of the transition state.