Methionine Cycle / Transmethylation (SAM Cycle, homocysteine)

1. 1

   L-methionine + ATP → S-adenosylmethionine (SAM) + Pᵢ + PPᵢ

   Methionine adenosyltransferase (MAT) ST-0170 Irreversible ATP Pi PPi SAM
   In Methionine ATP

   Out S-adenosylmethionine (SAM) Pi PPi
   › Notes

   Methionine adenosyltransferase (MAT; MAT I/III in adult liver, MAT II extrahepatically) transfers the adenosyl moiety of ATP to methionine. ATP is cleaved to tripolyphosphate equivalents (Pᵢ + PPᵢ, with PPᵢ hydrolysis driving the reaction); this is an essentially irreversible activation step that consumes three high-energy phosphate bonds.

2. 2

   SAM + methyl acceptor → S-adenosylhomocysteine (SAH) + methylated acceptor

   SAM-dependent methyltransferases ST-0171 Irreversible/directional SAM
   In S-adenosylmethionine (SAM)

   Out S-adenosylhomocysteine (SAH)
   › Notes

   A large family of SAM-dependent methyltransferases transfers the activated methyl group to substrates such as DNA, RNA, norepinephrine, phosphatidylethanolamine, guanidinoacetate, and catechols. No additional ATP is used in the transfer, but SAM cleavage makes methyl transfer strongly favorable; this is the defining transmethylation step.

3. 3

   SAH + H₂O ⇌ homocysteine + adenosine

   S-adenosylhomocysteine hydrolase (AHCY) ST-0172 Reversible H2O
   In S-adenosylhomocysteine H2O

   Out Homocysteine Adenosine
   › Notes

   S-adenosylhomocysteine hydrolase (AHCY) catalyzes a reversible reaction whose in vivo direction is driven toward hydrolysis by rapid removal of homocysteine and adenosine. SAH is a potent competitive inhibitor of many methyltransferases, so its clearance is necessary to preserve methylation potential.

4. 4

   Homocysteine + 5-methyl-THF → methionine + THF

   Methionine synthase (MTR) 2.1.1.13 ST-0173 Irreversible/directional Cobalamin (B12) THF (folate)
   In Homocysteine 5-Methyl-THF

   Out Methionine Tetrahydrofolate (THF)
   › Notes

   Methionine synthase (MTR) requires methylcobalamin (vitamin B12) and links the methionine cycle to the folate cycle. Reductive reactivation of oxidized cobalamin requires methionine synthase reductase, NADPH, FAD, FMN, and SAM; remethylation is the principal methionine-conserving route in most tissues.

5. 5

   Homocysteine + betaine → methionine + dimethylglycine

   Betaine–homocysteine methyltransferase (BHMT) 2.1.1.5 ST-0174 Irreversible/directional
   In Homocysteine Betaine

   Out Methionine Dimethylglycine
   › Notes

   Betaine–homocysteine methyltransferase (BHMT) uses betaine (trimethylglycine) as methyl donor in liver and kidney. This folate- and B12-independent alternative remethylation pathway is especially important when choline/betaine supply is adequate.

6. 6

   Homocysteine + L-serine → cystathionine + H₂O

   Cystathionine beta-synthase (CBS) 4.2.1.22 ST-0175 Irreversible rate-limiting PLP (B6) Heme/cytochrome H2O
   In Homocysteine Serine

   Out Cystathionine H2O
   › Notes

   Cystathionine β-synthase (CBS) uses PLP (vitamin B6) and a heme regulatory domain to catalyze the first transsulfuration step. It is the committed, essentially irreversible, rate-controlling step of transsulfuration and is activated by SAM when methionine/SAM abundance is high.

7. 7

   Cystathionine + H₂O → L-cysteine + α-ketobutyrate + NH₄⁺

   Cystathionine gamma-lyase (CGL/CSE) 4.4.1.1 ST-0176 Irreversible/directional PLP (B6) H2O
   In Cystathionine H2O

   Out Cysteine Alpha-ketobutyrate NH4+
   › Notes

   Cystathionine γ-lyase (CGL/CSE) is PLP-dependent and completes transsulfuration. α-Ketobutyrate is oxidatively decarboxylated to propionyl-CoA and can yield succinyl-CoA through the biotin- and cobalamin-dependent propionate pathway.

Showing all 7 steps.

Overview

The methionine cycle activates methionine to S-adenosylmethionine (SAM), the universal major methyl donor for DNA, RNA, protein, phospholipid, neurotransmitter, and small-molecule methylation. After methyl donation, SAM becomes S-adenosylhomocysteine (SAH), which is hydrolyzed to homocysteine. Homocysteine is either remethylated to methionine or committed to transsulfuration, producing cysteine and ultimately glutathione and sulfate.

Cellular location

Most methionine-cycle and transmethylation reactions occur in the cytosol of all cells, with especially high capacity in liver. The liver coordinates methionine conservation, SAM disposal, and transsulfuration; kidney also uses betaine-dependent remethylation. Mitochondria contain important one-carbon and SAM-dependent reactions, but the canonical methionine-cycle enzymes are largely cytosolic.

Net energetics

Formation of one SAM from methionine consumes 1 ATP equivalent cleaved to Pᵢ + PPᵢ, i.e., 3 high-energy phosphate bonds after pyrophosphate hydrolysis. Each methyl-transfer reaction consumes the activated methyl potential of one SAM but does not directly hydrolyze another ATP. Remethylation via methionine synthase uses a methyl group from 5-methyl-THF, whose formation requires NADPH through MTHFR; transsulfuration itself has no direct ATP requirement but irreversibly diverts methionine sulfur toward cysteine.

Clinical significance

SAM availability and the SAM:SAH ratio determine cellular methylation potential, affecting epigenetic regulation, neurotransmitter metabolism, phosphatidylcholine synthesis, and creatine synthesis. CBS deficiency causes classical homocystinuria, typically with markedly elevated homocysteine, thrombosis, ectopia lentis, skeletal abnormalities, and variable neurodevelopmental impairment; some variants respond to pyridoxine. Defects in remethylation (including B12, MTR, MTRR, or severe MTHFR deficiency) cause hyperhomocysteinemia with low or inappropriately normal methionine and may present with neurologic disease and megaloblastic anemia when B12 metabolism is involved.