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 class or drugs inhibit purine/pyrimidine synthesis and availability in the cells thereby decreases the cell replication. The inhibitors of 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 binds and irreversibly inhibit the enzymes are known as suicide inhibitors.

Thymidylate synthetase along other enzymes of purine metabolism utilizes folic acid for one carbon transfer reaction. The structural analogs of folate such as methotrexate that inhibits 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 the 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 crystal in soft tissues and joints of extremes. The accumulation of uric acid crystal in joints may lead to the inflammation, macrophage recruitment and result in for the formation of topi and gouty arthritis. In gout, the uric acid accumulation may be associated with either increased production or decreased excretion through the kidney. Allopurinol is the pharmacological agent that decrease the production of uric acid by inhibiting a key enzyme Xanthine Oxidase of its pathway.



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