[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Methionine cycle and transsulfuration [Biochemistry](https://durgical.com/en/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 ## Interactive map **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](https://durgical.com/en/biochemistry/molecules/methionine/) + [ATP](https://durgical.com/en/biochemistry/molecules/atp/) + H₂O → [S-adenosylmethionine](https://durgical.com/en/biochemistry/molecules/s-adenosylmethionine/) + phosphate (Pi) + pyrophosphate Moves 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](https://durgical.com/en/biochemistry/molecules/s-adenosylmethionine/) + Methyl acceptor (DNA, protein, phospholipid…) → [S-Adenosylhomocysteine](https://durgical.com/en/biochemistry/molecules/s-adenosylhomocysteine/) + Methylated product Hundreds 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](https://durgical.com/en/biochemistry/molecules/s-adenosylhomocysteine/) + H₂O ⇌ [Homocysteine](https://durgical.com/en/biochemistry/molecules/homocysteine/) + Adenosine Splits 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](https://durgical.com/en/biochemistry/enzymes/methionine-synthase/)** irreversible [Homocysteine](https://durgical.com/en/biochemistry/molecules/homocysteine/) + 5-Methyl-THF → [Methionine](https://durgical.com/en/biochemistry/molecules/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) →](https://durgical.com/en/conditions/megaloblastic-anaemia/) - **Exit · [Cystathionine β-synthase (CBS)](https://durgical.com/en/biochemistry/enzymes/cystathionine-synthase/)** irreversible [Homocysteine](https://durgical.com/en/biochemistry/molecules/homocysteine/) + Serine → Cystathionine + H₂O Joins 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 →](https://durgical.com/en/conditions/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](https://durgical.com/en/biochemistry/pathways/methionine-cycle-and-transsulfuration/) ## Related conditions - [Homocystinuria](https://durgical.com/en/conditions/homocystinuria/) - [Megaloblastic anaemia (B12 or folate deficiency)](https://durgical.com/en/conditions/megaloblastic-anaemia/) - [Pernicious anaemia](https://durgical.com/en/conditions/pernicious-anaemia/) - [Deep vein thrombosis](https://durgical.com/en/conditions/deep-vein-thrombosis/) ## Related - [Methionine](https://durgical.com/en/biochemistry/molecules/methionine/) - [S-adenosylmethionine (SAM)](https://durgical.com/en/biochemistry/molecules/s-adenosylmethionine/) - [S-Adenosylhomocysteine (SAH)](https://durgical.com/en/biochemistry/molecules/s-adenosylhomocysteine/) - [Homocysteine](https://durgical.com/en/biochemistry/molecules/homocysteine/) - [Methionine synthase](https://durgical.com/en/biochemistry/enzymes/methionine-synthase/) - [Cystathionine β-synthase (CBS)](https://durgical.com/en/biochemistry/enzymes/cystathionine-synthase/) - [One-carbon metabolism (folate, B12 and SAM)](https://durgical.com/en/biochemistry/topics/one-carbon-metabolism/) - [Folate (vitamin B9)](https://durgical.com/en/biochemistry/molecules/folate/) - [Cobalamin (vitamin B12)](https://durgical.com/en/biochemistry/topics/cobalamin/) - [Vitamin B6 (pyridoxal phosphate)](https://durgical.com/en/biochemistry/molecules/vitamin-b6/) - [Propionyl-CoA to succinyl-CoA](https://durgical.com/en/biochemistry/pathways/propionyl-coa-to-succinyl-coa/) ## 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. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/biochemistry/pathways/methionine-cycle-and-transsulfuration/) Educational information, not medical advice. For any symptom, see a health professional. Sources: [Homocystinuria: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/homocystinuria/) (MedlinePlus, US National Library of Medicine, 2026); [MTR gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/mtr/) (MedlinePlus, US National Library of Medicine, 2026); [MAT1A gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/mat1a/) (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). [← All of biochemistry](https://durgical.com/en/biochemistry/) ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/biochemistry/pathways/methionine-cycle-and-transsulfuration/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/pathways/methionine-cycle-and-transsulfuration/