Biochemistry · Metabolic pathway

Methionine cycle and transsulfuration !

Methionine is turned into SAM, the cell's main methyl donor. The leftover homocysteine is recycled to methionine or used to make cysteine.

Updated 2026-11-01

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Balance: ATP -1

Key facts

SAM (S-adenosylmethionine) gives methyl groups to DNA, phospholipids, creatine, epinephrine and many other acceptors; it then becomes SAH.
Methionine synthase remethylates homocysteine with vitamin B12 (methylcobalamin) and 5-methyl-THF: this joins the cycle to folate metabolism.
Cystathionine β-synthase (vitamin B6) sends homocysteine irreversibly to transsulfuration: cystathionine, then cysteine.
In the liver, betaine–homocysteine methyltransferase (BHMT) is a second, folate-independent way back to methionine.
SAM activates CBS and inhibits MTHFR, so an excess of methionine pushes homocysteine toward cysteine.

Also called: SAM cycle, Activated methyl cycle

Regulation

SAM is the switch: it activates CBS (the exit) and inhibits MTHFR, so less 5-methyl-THF is available for remethylation.
SAH strongly inhibits most methyltransferases; SAH hydrolase must remove it for methylation to go on.
In the liver, glycine N-methyltransferase (GNMT) spends excess SAM and keeps the SAM/SAH ratio steady.

The steps, one by one

Step 1 · Methionine adenosyltransferase (MAT1A liver, MAT2A other tissues) irreversible Methionine + ATP + H₂O → S-adenosylmethionine + phosphate (Pi) + pyrophosphateMoves the whole adenosyl part of ATP onto the sulfur of methionine, making SAM and releasing all three phosphates.If it fails: MAT1A deficiency: isolated hypermethioninaemia, usually without symptoms; a few patients have demyelination.
Step 2 · SAM-dependent methyltransferases (e.g. GNMT, PNMT, DNMT) irreversible S-adenosylmethionine + Methyl acceptor (DNA, protein, phospholipid…) → S-Adenosylhomocysteine + Methylated productHundreds of methyltransferases pass the methyl group of SAM to DNA, proteins, phospholipids, creatine or neurotransmitters, leaving SAH.If it fails: Too little SAM or too much SAH slows the methylation of DNA, myelin and neurotransmitters.
Step 3 · S-adenosylhomocysteine hydrolase (AHCY) S-Adenosylhomocysteine + H₂O ⇌ Homocysteine + AdenosineSplits SAH into homocysteine and adenosine; the equilibrium favours SAH, so the reaction moves forward only because both products are removed quickly.If it fails: AHCY deficiency (very rare): high SAH and methionine, muscle disease and liver damage.
Step 4 · Methionine synthase (MTR), B12-dependent irreversible Homocysteine + 5-Methyl-THF → Methionine + Tetrahydrofolate (THF)Moves the methyl of 5-methyl-THF, through methylcobalamin, onto homocysteine: methionine is remade and THF is freed for DNA synthesis.If it fails: Without B12, folate is trapped as 5-methyl-THF (methyl-folate trap): megaloblastic anaemia with high homocysteine. Megaloblastic anaemia (B12 or folate deficiency) →
Exit · Cystathionine β-synthase (CBS) irreversible Homocysteine + Serine → Cystathionine + H₂OJoins homocysteine to serine to form cystathionine; cystathionine γ-lyase (also B6) then releases cysteine and α-ketobutyrate.If it fails: CBS deficiency: classic homocystinuria with lens dislocation, thrombosis and osteoporosis; part of the patients respond to vitamin B6. Homocystinuria →

Clinical notes

Classic homocystinuria (CBS deficiency): downward lens dislocation, tall Marfan-like build, intellectual disability and thrombosis; some patients respond to vitamin B6.
B12 or folate deficiency raises plasma homocysteine; methylmalonic acid rises only with B12 deficiency, which tells them apart.
Mild hyperhomocysteinaemia is a marker of vascular risk and venous thrombosis.
Methotrexate (folate antagonist) and nitrous oxide (inactivates B12) can raise homocysteine.

Pathways

Methionine cycle and transsulfuration

Test yourself

Think of the answer, then tap the question to see it.

Which vitamin does cystathionine β-synthase need, and which disease follows its deficiency?

Vitamin B6 (pyridoxal phosphate). Its deficiency causes classic homocystinuria, and some patients improve with B6.

Why does B12 deficiency raise homocysteine?

Methionine synthase uses methylcobalamin to move the methyl of 5-methyl-THF onto homocysteine; without B12 homocysteine builds up and folate stays trapped.

What does SAM become after it gives away its methyl group?

S-adenosylhomocysteine (SAH), which SAH hydrolase splits into homocysteine and adenosine.

Which lab test helps separate B12 deficiency from folate deficiency?

Methylmalonic acid: it rises in B12 deficiency, because methylmalonyl-CoA mutase also needs B12, but not in folate deficiency. Homocysteine rises in both.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: Homocystinuria: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); MTR gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); MAT1A gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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