Pharmacological Inhibitor of Purine and Pyrimidine Metabolism

Pharmacological agents that directly or indirectly inhibit purine and pyrimidine synthesis have been used as anti-bacterial agents and anti-tumor drugs. These classes of drugs inhibit purine/pyrimidine synthesis and availability in the cells thereby decreasing cell replication. The inhibitors of the purine degradation pathway are used for the treatment of gout.

Anti-tumor agents
Fluorouracil is a mechanism-based drug that inhibits the enzyme Thymidylate synthetase (TS). Thymidylate synthetase is an enzyme that catalyzes the synthesis of deoxyuridine monophosphate to deoxythymidine monophosphate, a building block of DNA. The inhibitor of the enzyme led to decreased production of dTMP and reduced substrate for DNA replication and cell cycle. 
5-Fluorouracil competes with uracil to bind enzyme TS. 5-fluorouracil is metabolically converted to 5-FdUMP which covalently binds to the enzyme and inactivates it. These types of inhibitors that competitively bind and irreversibly inhibit the enzymes are known as suicide inhibitors.

Thymidylate synthetase along with other enzymes of purine metabolism utilizes folic acid for a one-carbon transfer reaction. The structural analogs of folate such as methotrexate inhibit the enzyme Dihydrofolate reductase also serves as an anti-cancer drug. The inhibition of dihydrofolate reductase decreases the recycling of dihydrofolate to tetrahydrofolate, an active 1-carbon acceptor molecule.

Antibacterial agents:
Sulfonamides and Trimethoprim are selective inhibitors of bacterial enzymes. Sulfonamides are the structural analogs of para-aminobenzoic acid that competitively inhibit bacterial synthesis of folic acid synthesis in bacteria. 
Trimethoprim inhibits the recycling of dihydrofolate to tetrahydrofolate by selectively inhibiting bacterial dihydrofolate reductase.

Treatment of Gout:
Gout is a disorder associated with the deposition of uric acid crystals in soft tissues and joints of extremes. The accumulation of uric acid crystals in joints may lead to inflammation, macrophage recruitment and result in the formation of topi and gouty arthritis. 
In gout, uric acid accumulation may be associated with either increased production or decreased excretion through the kidney.  
Allopurinol is the pharmacological agent that decreases the production of uric acid by inhibiting the key enzyme Xanthine Oxidase of its pathway.



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