Dihydrofolate reductase enzyme in Plasmodium species (DHFR)

Dihydrofolate reductase is a key enzyme found in all organisms that catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid using NADPH as an electron donor. In Plasmodium species—the causative agents of malaria—this enzyme is essential for folate metabolism and de novo synthesis of purines and thymidylic acid required for DNA replication. The Plasmodium DHFR is a validated therapeutic target because it differs structurally from human DHFR; this allows selective inhibition by antimalarial drugs such as pyrimethamine and cycloguanil. However, widespread use has led to resistance through specific point mutations within the parasite's dhfr gene. Newer inhibitors like P218 have been developed with improved selectivity against both wild-type and resistant forms of Plasmodium DHFR while sparing human DHFR activity. The bifunctional nature of this protein—combining dihydrofolate reductase with thymidylate synthase activity—is notable in some Plasmodium species.

Other names

DHFRDihydrofolate reductase-thymidylate synthase (in some Plasmodium species, the gene is bifunctional and encodes both activities)PfDHFR (for Plasmodium falciparum dihydrofolate reductase)

Competitive inhibition of the active site, blocking reduction of dihydrofolic acid to tetrahydrofolic acid, thereby inhibiting DNA synthesis and cell division in the parasite