remethylation

Remethylation refers to the biochemical process by which a methyl group is transferred to a substrate, most commonly the conversion of homocysteine to methionine. This reaction regenerates methionine for protein synthesis and, crucially, for the formation of S-adenosylmethionine (SAM), the universal methyl donor used in many cellular methylation reactions including DNA, RNA, and protein methylation.

Two primary pathways supply the methyl group to homocysteine. The folate and vitamin B12–dependent pathway is catalyzed by methionine synthase (MS). In this reaction, 5-methyl-tetrahydrofolate donates a methyl group to homocysteine, with cobalamin (B12) as a cofactor, yielding methionine and regenerating tetrahydrofolate (THF). A second pathway, mainly in liver and kidney, uses betaine as the methyl donor via the enzyme betaine-homocysteine methyltransferase (BHMT). The BHMT reaction converts homocysteine to methionine and produces dimethylglycine, and it does not require B12.

Remethylation operates in concert with the transsulfuration pathway, which irreversibly converts homocysteine to cystathionine via cystathionine beta-synthase and vitamin B6, thereby maintaining balance in the methionine cycle. Disruptions of remethylation—nutritional folate or B12 deficiency, or genetic defects in MTR, MTRR, or MTHFR—can elevate homocysteine levels (hyperhomocysteinemia) and are associated with cardiovascular and developmental disorders. Treatment typically focuses on correcting vitamin deficiencies and, in some cases, modifying methyl-donor availability through diet or supplements.