Folate-dependent one-carbon cycle. (A and B) Outline of the major steps within the one-carbon cycle that shuttles single-carbon units on different folate metabolites in the mitochondria (A) and the cytoplasm (B). (C) The folate-dependent one-carbon cycle is intrinsically linked to the methionine cycle through 5-methylTHF. The major products of the one-carbon cycle are nucleotides for DNA replication and maintenance, SAM as the methyl donor for methylation reactions, and homocysteine contributes to glutathione synthesis via the transsulfuration pathway. AHCY, adenosylhomocysteinase; AICARTF, aminoimidazolecarboxamide ribonucleotide transformylase; DHF, dihydrofolate; DHFR, dihydrofolate reductase; dUMP, deoxyuridine monophosphate; GARTF, glycinamide ribonucleotide transformylase; MTHFD, methylenetetrahydrofolate dehydrogenase; MTHFD1L, methylenetetrahydrofolate dehydrogenase 1–like; MTHFR, methylene-tetrahydrofolate reductase; MTR, methionine synthase; MTs, methyltransferases; SHMT, serine hydroxymethyltransferase; TYMS, thymidylate synthase; dUMP, deoxyuracil monophosphate.