Figure 1.

Overview of one-carbon metabolism. Folic acid (used in fortified foods and supplements) is reduced to dihydrofolate (DHF) and tetrahydrofolate (THF) by dihydrofolate reductase (DHFR). A methyl group is then transferred from serine to THF by serine hydroxymethyltransferase (SHMT), forming 5,10-methylene-THF and glycine. 5,10-methylene-THF can be reduced by 5,10-methylene tetrahydrofolate reductase (MTHFR) to 5-methyl-THF. The methyl group of 5-methyl-THF, the predominant naturally occurring form in dietary sources, is transferred to homocysteine by methionine synthase (MS), generating methionine and regenerating THF. Vitamin B₁₂ is a cofactor for MS. Methionine can also be generated independently of folate and B₁₂, by the action of betaine-homocysteine methyltransferase (BHMT), which transfers a methyl group from betaine to homocysteine. Methionine is then activated by methionine adenosyltransferase (MAT) to form S-adenosylmethionine (SAM), which serves as a universal methyl donor for numerous reactions, including the conversion of inorganic arsenic to methylated arsenicals (by arsenic methyltransferase; AS3MT), guanidinoacetate (GAA) to creatine (by guanidinoacetate methyltransferase; GAMT), and many others. The products of these methylation reactions are the methylated substrate and S-adenosylhomocysteine (SAH). SAH is subsequently hydrolyzed by SAH hydrolase (SAHH) to generate homocysteine. Homocysteine is then used either to regenerate methionine, or it is directed to the transsulfuration pathway.