Definition: The Dihydrofolate reductase, or DHFR, reduces dihydrofolic acid (DHF) to tetrahydrofolic acid (THF), using NADPH as electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry.
Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids.
Because tetrahydrofolate (THF) is the active form of folate in humans, inhibition of DHFR by various drugs can cause functional folate deficiency.
Because folate is needed by rapidly dividing cells to make thymine, this effect may be therapeutic. For example, methotrexate is used as cancer chemotherapy because it can prevent neoplastic cells from dividing.
A variety of drugs act on dihydrofolate reductase (antifolic drugs):
the chemotherapeutic agents methotrexate, raltitrexed and pemetrexed.
the antibiotic trimethoprim.
the antimalarial drug pyrimethamine.
the experimental new antimalarial drug JPC-2056, which also works much better against toxoplasmosis.
Methotrexate, the first anticancer drug, acts on this enzyme binding to it some 1000 times more tightly than folate itself.
Pathology
Deficiency of the enzyme may be a cause of folate deficiency, and therefore of megaloblastic anemia.