S-adenosylmethionine (SAM) cycle — SAM synthesis / transmethylation / SAH hydrolysis (MAT1A/GNMT/AHCY); hypermethioninemias

The S-adenosylmethionine (SAM) arm of the methionine cycle generates and recycles the universal biological methyl donor. Methionine adenosyltransferase (liver MAT1A; extrahepatic MAT2A) condenses L-methionine with ATP to form S-adenosyl-L-methionine (SAM). SAM then donates its methyl group in the many transmethylation reactions of SAM-dependent methyltransferases — of which glycine N-methyltransferase (GNMT), the abundant hepatic enzyme methylating glycine to sarcosine, is the major regulator of the SAM:SAH ratio (cellular methylation capacity) — each producing S-adenosyl-L-homocysteine (SAH). Adenosylhomocysteinase (AHCY, SAH hydrolase) then hydrolyses SAH to L-homocysteine + adenosine, relieving the potent SAH product-inhibition of methyltransferases. Homocysteine is then either remethylated back to methionine (methionine synthase MTR / betaine-homocysteine methyltransferase), closing the cycle, or committed to transsulfuration (CBS) toward cysteine — reactions curated in the homocysteine-metabolism module. Inherited defects of the three SAM-arm enzymes all cause hypermethioninemia: MAT1A (MAT I/III deficiency, usually benign, severe forms with CNS demyelination), GNMT (GNMT deficiency, mild hepatopathy), and AHCY (S-adenosylhomocysteine hydrolase / SAHH deficiency, with elevated SAH/SAM, myopathy, developmental delay and liver disease).