Category: biosynthesis
Folate (folic acid → DHF → THF) is reduced via DHFR — the methotrexate target. THF accepts one-carbon units (from serine, glycine, formate) at the N5/N10 positions to form: 5-methyl-THF (donates methyl to homocysteine → methionine), 5,10-methylene-THF (donates methyl to dUMP → dTMP via thymidylate synthase — the 5-FU target), 10-formyl-THF (donates formyl to purine de novo synthesis). Methotrexate inhibits DHFR + thymidylate synthase + AICAR transformylase — explaining its activity in chemotherapy (kills proliferating cells), rheumatology (immunosuppressant), and obstetrics (ectopic pregnancy + medical abortion). Leucovorin (5-formyl-THF) bypasses DHFR for rescue.