Roles of vitamin B12 and folate in the methionine cycle, folate cycle, and DNA synthesis showing the methyl folate "trap"

The roles of vitamin B12 and folate in the methionine cycle, folate cycle, and DNA synthesis are shown. The key intersection of vitamin B12 and folate occurs at the methionine synthase (MS) reaction (shown at the left edge between the yellow and blue panels) in which the one-carbon methyl group of methyl-tetrahydrofolate (methylTHF) is transferred to homocysteine to form methionine. Vitamin B12 (as methylcobalamin) acts as a cofactor for this reaction. Tetrahydrofolate regains a one-carbon methylene group through the serine-hydroxymethyltransferase (SHMT) reaction, and the resulting methylenetetrahydrofolate (methyleneTHF) is essential for conversion of deoxyuridine to thymidine in the thymidylate synthase (TS) reaction, which is rate-limiting for DNA synthesis. In vitamin B12 deficiency, folate becomes trapped as methylTHF (the methyl folate "trap"). Administration of folic acid can temporarily overcome this block through formation of tetrahydrofolate (THF). The other product of the MS reaction is the essential amino acid methionine, which becomes adenosylated and serves as a universal methyl donor in numerous methyltransferase reactions. The product S-adenosyl-homocysteine (SAH) undergoes reversible hydrolysis, completing the methionine (or remethylation) cycle. The alternative pathway for Hcy disposal, which involves transsulfuration and requires vitamin B6, is not shown.