Methionine is the methyl-group donor source: methionine → SAM (S-adenosylmethionine; MAT) → SAH (S-adenosylhomocysteine; after methyl transfer) → homocysteine (SAH hydrolase) → methionine (methionine synthase, B12 + 5-methyl-THF dependent) or → cystathionine → cysteine (B6-dependent transsulfuration). B12 OR folate deficiency raises homocysteine; chronically elevated homocysteine is a CV risk marker. MTHFR C677T polymorphism reduces 5,10-methylene-THF → 5-methyl-THF flux, raising homocysteine in homozygotes.
Organ Systems
nervous
cardiovascular
immune-hematologic
Pathway Steps
methionine → s-adenosylmethionine — via methionine adenosyltransferase (MAT). Methionine adenosyltransferase makes SAM, the universal methyl donor (a high-energy sulfonium). SAM also feeds polyamine synthesis and allosterically activates CBS — steering homocysteine toward disposal when methyl status is high.
s-adenosylmethionine → s-adenosylhomocysteine — via methyl transfer to acceptor substrates (DNA, histones, neurotransmitters). Hundreds of methyltransferases (COMT, PEMT, DNA/histone enzymes…) transfer SAM’s methyl group, producing SAH. SAH is a potent product-inhibitor of those enzymes, so the SAM:SAH ratio (the “methylation index”) gauges methylation capacity.
s-adenosylhomocysteine → homocysteine — via SAH hydrolase. SAH hydrolase reversibly releases homocysteine and adenosine, and the equilibrium actually favors synthesis — so it proceeds only when both products are cleared downstream, making homocysteine disposal the pull that keeps methylation running.
homocysteine → methionine — via methionine synthase — B12 + 5-methyl-THF cofactors. Methionine synthase remethylates homocysteine using 5-methyl-THF and a vitamin-B12 (methylcobalamin) cofactor — where folate and B12 status converge. B12 deficiency traps folate as 5-methyl-THF (the “methyl-folate trap”), causing a functional folate deficiency.
homocysteine → cystathionine — via CBS — B6 cofactor; transsulfuration branch. The transsulfuration alternative: CBS (B6-dependent, SAM-activated) routes homocysteine to cysteine/glutathione rather than remethylation. The remethylation-vs-transsulfuration balance sets plasma homocysteine, elevated in B12/folate/B6 deficiency and CBS defects.
methylfolate (cofactor) — homocysteine remethylation (methionine synthase). 5-MTHF donates its methyl group to homocysteine via methionine synthase (B12-dependent), forming methionine + THF; bypasses MTHFR for those with reduced enzyme activity.
methylcobalamin (cofactor) — methionine synthase (transient methyl carrier on cobalt). Active B12 form; the cobalt center holds the methyl group transiently between 5-MTHF and homocysteine.
cyanocobalamin (cofactor) — intracellular B12 pool → methylcobalamin (methionine synthase). Synthetic B12 precursor; cellular processing removes the cyanide and forms the active methyl- and adenosyl-cobalamin coenzymes.