Dihydrofolate reductase from Pneumocystis carinii (DHFR)

Dihydrofolate reductase from Pneumocystis carinii is an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) using NADPH as a cofactor, which is essential for folate metabolism and nucleotide synthesis. In the context of human health, this enzyme is a validated drug target for treating Pneumocystis pneumonia in immunocompromised patients, particularly those with HIV/AIDS. The enzyme's structural features and its interaction with several inhibitor classes (especially trimethoprim and related antifolates) have been extensively studied by X-ray crystallography to inform the design of potent, selective antifungal agents. Notable therapeutic challenges include limited drug selectivity versus human DHFR, with potential for toxicity and resistance, motivating ongoing efforts to develop improved inhibitors.

Other names

Pneumocystis carinii DHFRpcDHFRDihydrofolate reductase (Pneumocystis carinii)DHFR (Pneumocystis)FolA (by gene ontology, less common for fungal species)

Competitive inhibition of DHFR: drugs such as trimethoprim, methotrexate, and pyrido[2,3-d]pyrimidines competitively bind to the active site, preventing reduction of dihydrofolate to tetrahydrofolate, thus inhibiting nucleic acid synthesis and cell replication