Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in one-carbon transfer chemistry. DHFR mutations cause dihydrofolate reductase deficiency, a rare autosomal recessive inborn error of folate metabolism that results in megaloblastic anemia, pancytopenia and severe cerebral folate deficiency. These issues can be overcome by supplementation with a reduced form of folate, usually folinic acid. DHFR is an attractive pharmaceutical target for inhibition due to its pivotal role in DNA precursor (thymine) synthesis. Trimethoprim, an antibiotic, inhibits bacterial DHFR while methotrexate, a chemotherapy agent, inhibits mammalian DHFR.
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