S-Adenosylmethionin (SAM): the pathway in the body

S-Adenosylmethionin (SAM) is part of the pathway “Methylation: methionine and homocysteine”. This page shows the whole pathway; the station of S-Adenosylmethionin (SAM) is highlighted.

Where this laboratory value sits: SAM — S-adenosylmethionine. The enzyme MAT joins methionine with ATP to form S-adenosylmethionine. SAM is the compound from which the cell draws methyl groups – small carbon building blocks. SAM is thus the central methyl group donor and also inhibits MTHFR. Source 7, 1

In brief

Methionine and homocysteine are sulphur-containing amino acids in a cycle that supplies methyl groups. Methionine forms SAM, which donates methyl groups to DNA, proteins and messengers; with folate and vitamin B12, homocysteine is turned back into methionine. SAH slows the cycle.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Methionine → SAM MAT · ATP, Magnesium The enzyme MAT joins methionine with ATP to form S-adenosylmethionine. SAM is the compound from which the cell draws methyl groups – small carbon building blocks. SAM is thus the central methyl group donor and also inhibits MTHFR. Source 7, 1↑ supplies SAM is the cell's main methyl group donor: methyltransferases transfer its methyl group to DNA, proteins, lipids and messengers. SAM also steers the cycle: it inhibits MTHFR and activates CBS. established physiology Source 7, 1
   ⚖ When the balance tips

   too much — If SAM builds up, it inhibits MTHFR and activates CBS: less homocysteine is returned, more goes to cysteine. In the liver, glycine N-methyltransferase removes surplus SAM.

   too little — If little SAM is available, the methyltransferases have fewer methyl groups to work with; the brake on MTHFR loosens, and the route from homocysteine back to methionine runs more strongly.

   established physiology · Source 1, 7

2. SAM → SAH Methyltransferases Methyltransferases transfer the methyl group from SAM to DNA, proteins and messengers. What remains is S-adenosylhomocysteine. If SAH builds up, it inhibits the methyltransferases. Source 1, 3↓ depletes SAH binds to the methyltransferases and inhibits them; the ratio of SAM to SAH helps determine how much methylation takes place. SAH hydrolase keeps SAH low by splitting it into homocysteine and adenosine. established physiology Source 1, 7
   ⚖ When the balance tips

   too much — If SAH builds up, it inhibits many methyltransferases at once, and the methylation of DNA, proteins and messengers slows down. Because the splitting is reversible, SAH rises when homocysteine builds up.

   too little — If little SAH is present, it barely slows the methyltransferases; how much methylation takes place then depends mainly on the supply of SAM.

   established physiology · Source 1, 7

3. 5,10-Methylene-THF → 5-Methyl-THF MTHFR · Vitamin B2 (FAD), NADPH MTHFR converts 5,10-methylene-THF into 5-methyl-THF. The common gene variant C677T results in a less stable enzyme that works more slowly. SAM inhibits MTHFR and so throttles the supply. Source 4, 2↑ supplies 5-methyl-THF donates its methyl group to homocysteine via methionine synthase. Only by this route does this folate form return to the rest of the folate cycle. established physiology Source 2, 4
   ⚖ When the balance tips

   too much — If 5-methyl-THF builds up because methionine synthase cannot proceed without vitamin B12, folate stays bound in this form and is unavailable to the other folate routes (methyl trap).

   too little — If little 5-methyl-THF is available, for instance because MTHFR works more slowly, methionine synthase receives fewer methyl groups, and homocysteine is returned to methionine more slowly.

   established physiology · Source 2, 4

4. Homocysteine → Methionine renewed Methionine synthase · Vitamin B12 Methionine synthase transfers the methyl group from 5-methyl-THF to homocysteine. Vitamin B12 is the cofactor here; this closes the cycle. In the liver, a second route back runs via betaine. Source 2↑ supplies Remethylation conserves methionine: the same sulphur atoms pass through the cycle several times. Besides methionine synthase, the liver has a second route back via BHMT, which uses the methyl group of betaine. established physiology Source 2, 1
   ⚖ When the balance tips

   too much — If remethylation runs abundantly, SAM rises; SAM then inhibits MTHFR and activates CBS, so that more homocysteine enters the route to cysteine.

   too little — If little vitamin B12 or 5-methyl-THF is available, methionine synthase cannot keep up; homocysteine builds up, and in the liver the betaine route handles part of the remethylation.

   established physiology · Source 1, 2

5. Homocysteine → Cystathionine CBS · Vitamin B6 (PLP), Serine The second route is called transsulphuration. Cystathionine β-synthase joins homocysteine with serine; it works with pyridoxal phosphate, the active form of vitamin B6. SAM activates CBS. Source 5↑ supplies The formation of cystathionine is the step with no way back: what CBS joins with serine is withdrawn from the methyl cycle and heads towards cysteine. SAM activates CBS. established physiology Source 5, 1
   ⚖ When the balance tips

   too much — If cystathionine builds up because cystathionine γ-lyase cannot keep up, less cysteine forms from it, and the building blocks stay bound in the intermediate.

   too little — If little vitamin B6 is available, CBS works more slowly: less homocysteine enters the route to cysteine and glutathione, more stays in the cycle or builds up.

   established physiology · Source 5

6. Cystathionine → Cysteine Cystathionine γ-lyase · Vitamin B6 (PLP) Cystathionine γ-lyase splits cystathionine, producing cysteine. This enzyme also uses pyridoxal phosphate. When little B6 is available, cysteine forms more slowly. Source 5↑ supplies Cysteine supplies the sulphur for glutathione and proteins; in the cell it is usually the scarcest building block for glutathione. Cystathionine γ-lyase also forms the signalling molecule hydrogen sulphide from cysteine. established physiology Source 6, 5
   ⚖ When the balance tips

   too much — If a lot of cysteine arrives, the cell forms more glutathione until glutathione itself slows GCL; more cysteine then yields hardly any more glutathione.

   too little — If little cysteine is available, GCL forms less glutathione, because cysteine is the scarcest building block. If little B6 is available, the route from homocysteine to cysteine runs more slowly.

   established physiology · Source 6, 5

7. Cysteine → Glutathione GCL and GS · Glutamate, glycine, ATP Two enzymes link cysteine with glutamate and glycine to form glutathione, the most abundant sulphur-containing molecule in the cell. Each step uses ATP. It captures reactive oxygen species. Source 6↑ supplies Glutathione captures reactive oxygen species, keeps sulphur groups in proteins reduced and binds foreign substances for excretion. In doing so it is oxidised and recovered using NADPH. established physiology Source 6
   ⚖ When the balance tips

   too much — If plenty of glutathione is present, it inhibits GCL and so slows its own formation; the pool levels off.

   too little — If little glutathione is present, reactive oxygen species persist longer and foreign substances are bound more slowly; the inhibition of GCL eases, and the cell makes more as far as cysteine allows.

   established physiology · Source 6

Further stations

• Methionine — amino acid from food Methionine is a sulphur-containing amino acid. The body cannot build it itself; it comes from dietary protein and from the turnover of the body's own proteins. It is the starting material for SAM. Source 1↑ supplies Methionine is the starting material for SAM and thus for the cell's methyl groups; the cell also builds it into proteins. The liver turns over a particularly large share of methionine. established physiology Source 7, 1
  ⚖ When the balance tips

  too much — If a lot of methionine arrives, the liver forms more SAM; glycine N-methyltransferase passes surplus methyl groups to glycine, and more homocysteine enters the route to cysteine.

  too little — If little methionine is available, SAM falls; the inhibition of MTHFR eases, and homocysteine is preferentially returned to methionine instead of being broken down to cysteine.

  established physiology · Source 1, 7

• 5,10-Methylene-THF — folate form Folate from food exists in the cell in several forms. 5,10-methylene-THF carries a one-carbon unit (methylene group) that can still be passed on. It also serves to build the DNA building block thymidine. Source 3↑ supplies 5,10-methylene-THF is a switch point: it supplies the one-carbon unit for thymidine, a DNA building block, or MTHFR converts it into 5-methyl-THF for the methyl cycle. established physiology Source 3, 4
  ⚖ When the balance tips

  too much — If plenty of 5,10-methylene-THF is available, it suffices for thymidine and for MTHFR at the same time; how much enters the methyl cycle is set by MTHFR, which SAM inhibits.

  too little — If little 5,10-methylene-THF is available, thymidine synthesis for DNA and the formation of 5-methyl-THF draw on the same scarce pool; both routes run more slowly.

  established physiology · Source 3, 4

• Homocysteine — amino acid without methyl SAH hydrolase splits adenosine off SAH, leaving homocysteine. From here, two routes lead on: back to methionine or onward to cysteine. If homocysteine builds up, SAH rises with it. Source 1, 5↕ both, depending on amount Homocysteine is a distribution point: methionine synthase and, in the liver, BHMT with betaine lead back to methionine, CBS leads on to cysteine. If it builds up, SAH also rises via the reversible splitting. established physiology Source 1, 5
  ⚖ When the balance tips

  too much — If homocysteine builds up, the splitting of SAH runs backwards and SAH rises with it; this inhibits the methyltransferases. The cell also releases surplus homocysteine into the blood, where it becomes measurable.

  too little — If little homocysteine is present, SAH hydrolase runs freely in the splitting direction and SAH is cleared quickly; less starting material then reaches the route to cysteine.

  established physiology · Source 1

• Betaine — from choline, trimethylglycine Betaine comes from food or is formed from choline in the liver and kidney. In the liver it donates a methyl group to homocysteine via the enzyme BHMT; this is a second route back to methionine, independent of folate and vitamin B12. Source 8, 9↑ supplies Betaine supplies methyl groups with which the liver turns homocysteine back into methionine. It also holds water in cells as an osmolyte, for example in the renal medulla. established physiology Source 8, 9
  ⚖ When the balance tips

  too much — If much betaine or choline arrives, the liver turns more homocysteine back into methionine via BHMT; what is left over passes into the urine.

  too little — If little betaine or choline arrives, the BHMT route contributes less, and the regeneration of methionine depends more on the route via folate and vitamin B12.

  established physiology · Source 8, 9

Cofactors in this pathway

• Folate — As 5-methyl-THF, supplies the methyl group that turns homocysteine into methionine; if scarce, homocysteine builds up Source 2, 3In the ORY catalogue as a laboratory value: Folsäure
• Vitamin B12 — Cofactor of methionine synthase, which transfers the methyl group from folate to homocysteine; else the cycle stalls Source 2In the ORY catalogue as a laboratory value: Vitamin B12
• Vitamin B6 — As pyridoxal phosphate, cofactor of CBS and cystathionine gamma-lyase; if scarce, the route to cysteine runs slower Source 5In the ORY catalogue as a laboratory value: Vitamin B6
• Vitamin B2 (FAD) — As FAD, cofactor of MTHFR, which forms 5-methyl-THF; with little FAD, MTHFR works more slowly Source 4
• Magnesium — Accompanies ATP in MAT, which converts methionine to SAM; without ATP no SAM forms Source 7In the ORY catalogue as a laboratory value: Magnesium
• Serine — Joined with homocysteine by CBS to form cystathionine; this step removes homocysteine from the cycle Source 5In the ORY catalogue as a laboratory value: Serin
• Glycine — Building block of glutathione, together with cysteine and glutamate; glutathione captures reactive oxygen species Source 6In the ORY catalogue as a laboratory value: Glycin
• Betaine — Methyl group donor for BHMT, a second route back to methionine in the liver; works without folate and B12 Source 1

Sources

1. Selhub J. Homocysteine metabolism. Annu Rev Nutr 1999 · PubMed 10448523
2. Froese DS, Fowler B et al. Vitamin B12, folate, and the methionine remethylation cycle — biochemistry, pathways, and regulation. J Inherit Metab Dis 2019 · PubMed 30693532
3. Ducker GS, Rabinowitz JD. One-Carbon Metabolism in Health and Disease. Cell Metab 2017 · PubMed 27641100
4. Blomgren LKM, Guo S, Froese DS. 5,10-Methylenetetrahydrofolate Reductase — the Key Allosteric Regulator in One-Carbon Metabolism. Biochemistry 2026 · PubMed 41758688
5. Sbodio JI, Snyder SH, Paul BD. Regulators of the transsulfuration pathway. Br J Pharmacol 2019 · PubMed 30007014
6. Lu SC. Glutathione synthesis. Biochim Biophys Acta 2013 · PubMed 22995213
7. Lu SC. S-Adenosylmethionine. Int J Biochem Cell Biol 2000 · PubMed 10762064
8. Ueland PM. Choline and betaine in health and disease. J Inherit Metab Dis 2011 · PubMed 20446114
9. Craig SA. Betaine in human nutrition. Am J Clin Nutr 2004 · PubMed 15321791

Whole pathway: Methylation: methionine and homocysteine

Related pathways

• Glutathione — homocysteine
• Vitamin B12 — methionine
• Taurine — methionine
• Vitamin B6 — homocysteine
• Folic acid — 5,10-methylene-thf

As of 2026-09-16. Draft written by Claude to schema v2; sources checked in PubMed; expert review pending
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