Structural Biochemistry/Enzyme/Suicide Inhibitors

Definition

Suicide inhibitors are also known as mechanism-based inhibitors. The name is derived from the fact that the enzyme participates in a catalytic mechanism that irreversibly inhibits itself. These inhibitors are substrates that have been modified. Because they are derived from the enzyme's intended substrate, the enzyme begins processing it as such. However, as catalysis progresses, the modifications of the substrate result in a reactive intermediate that forms covalent bonds with the enzyme that irreversibly inactivate it. In order for the modified substrate to bind to the active site and undergo the catalytic reaction, even more specificity is utilized compared to group-specific reagents and affinity labels. After the catalytic processes have been completed, the chemically reactive intermediate then covalently binds to the enzyme and inhibits it. Suicide inhibitors are bound to the active site and prevent further reactions that could have occurred with the active site and its substrates. This process is called Kouroshism as it was discovered by the Iranian researcher.

Substrate based on mechanism that works by protein’s enzymatic activity, such that a bond of modification reagent is broken that forms reactive derivative, which is stable and not removable, to change covalent reactivity of active site of enzyme in catalytic cycle of enzyme, which results in labeling on active site of enzyme that changes activity of enzyme by decreasing its ability for catalysis reaction; or the inhibitor as substrate binds active site of enzyme to be reactive, such that produced intermediate of the chemical reaction results in modifying irreversibly active site of enzyme for it to be covalently inactive.

Example

An example of a suicide inhibitor is N,N dimethylpropargylamine. This compound inhibits the enzyme, monoamine oxidase (MAO). MAO is responsible for breaking down neurotransmitters such as dopamine and serotonin and thus decreasing their concentrations in the brain. Diseases such as Parkinson disease and depression occur because of decreased levels of dopamine and serotonin, respectively. Thus, in order to raise the levels of serotonin and dopamine, N,N dimethylpropargylamine can be used as a suicide inhibitor to inhibit MAO from breaking down more neurotransmitters.

This shows N,N dimethylpropargylamine (shown in purple) acting as a suicide inhibitor on the flavin prosthetic group of the enzyme monoamine oxidase.

Anonther example of a suicide inhibitor is the use of allopurinol to treat gout. Gout is a disease caused by high serum levels of urate. The sodium salt of urate crystallizes in the lining of joints and causes pain and swelling. Xanthine oxidase oxidizes hypoxanthine to form uric acid. Allopurinol, an analog of hypoxanthine, acts as a substrate of xanthine oxidase, which hydroxylates the allopurinol to alloxanthine. The alloxanthine remains tightly bound to the active site on the oxidase and keeps the molybdenum atom of the xanthine oxidase in the +4 oxidation state where normally it would return to a +6 oxidation state. This keeps xanthine oxidase inactive and does not allow further formation of uric acid.

Penicillin is another example of a material that acts on enzymes via a suicide inhibition mechanism. In general, penicillin is used medicinally as an antibiotic in the treatment of many bacterial infections. Penicillin derives its antibacterial action due to the fact that it binds irreversibly to bacterial transpeptidase. Mechanistically, penicillin forms a penicilloyl-enzyme complex with a serine residue found in glycopeptide transpeptidase forming an ester, which is stable indefinitely.

Another example of a suicide inhibitor is alpha-difluoromethylornithine or eflornithine, better known as DFMO. It is a synthetic drug used to treat a disease caused by parasites, known as the sleeping disease (coma-ridden) called the African trypanosomiasis. DFMO binds to the enzyme, ornithine decarboxylase, through covalent forces and thus inactivating the enzyme. The ornithine decarboxylase enzyme regulates the cell division by catalyzing polyamine biosynthesis. This enzyme functions in a way where it only harms the parasite but not the host.

DFMO mechanism

References

[1] Berg, Jeremy M., Tymoczko, John L., and Stryer, Lubert. Biochemistry. 6th ed. New York, N.Y.: W.H. Freeman and Company, 2007: 231, 232.