Dihydrofolate reductase, or DHFR, reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. Because tetrahydrofolate, the product of this reaction, is the active form of folate in humans, inhibition of DHFR 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, including the antibiotic trimethoprim, the antimalarial drug pyrimethamine, and the chemotherapeutic agents methotrexate and pemetrexed. The first anticancer drug, Aminopterin(methotrexate), acts on this enzyme, binding some 1000 times more tightly to the enzyme than folate itself. Deficiency of the enzyme may be a cause of folate deficiency, and therefore of megaloblastic anemia. Treatment is with reduced forms of folic acid.

External links

• 1988 Nobel lecture in Medicine

EC 1.5.1 | Enzymes