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Clinical Diagrams → Methylation Cycle

Biochemical Process Diagram

The Methylation Cycle
Enzymes · Cofactors · Outputs

The methylation cycle runs over a billion times per second in every cell. This diagram shows the complete cycle — key metabolites, enzymes at each step, essential nutrient cofactors, and what breaks down when the cycle stalls. Hover over any element for detail.

Cycle metabolites
Enzymes
Nutrient cofactors
Downstream outputs
Related pathways
The Methylation Cycle DETECTIVE HEALTH · STEPHEN DUNCAN FDN-P Methionine Essential amino acid CYCLE START SAM S-adenosylmethionine METHYL DONOR SAH S-adenosylhomocysteine AFTER DONATION Homo- cysteine BIFURCATION POINT MAT Methionine adenosyltransferase COMT / DNMT Methyltransferases SAHH SAH hydrolase MTR / MS Methionine synthase 5-MTHF Active folate methyl donor MTHFR Methylenetetra- hydrofolate reductase C677T · A1298C Dietary folate ↓ Food folate / 5-MTHF Synthetic folic acid ↓ requires MTHFR CBS Transsulphuration Cysteine → Glutathione Detoxification pathway DNA Methylation Gene expression · Epigenetics Cancer suppressor genes Neurotransmitters Serotonin · Dopamine Noradrenaline · Adrenaline Energy & Membranes Creatine synthesis (~70%) Phospholipids · CoQ10 B12 B2 / FAD Zinc Magnesium MTRR Elevated Homocysteine Risk Cardiovascular disease · Thrombosis Depression · Cognitive decline Neural tube defects · Pregnancy loss When remethylation OR transsulphuration stalls Oestrogen Methylation COMT: 2-OHE1 → 2-MeOE1 Slow COMT → oestrogen excess Visible on DUTCH hormone panel TESTABLE MARKERS Homocysteine (blood) · Methylmalonic acid (OAT) · FIGLU (OAT) · 2-MeOE1 / oestrogen methylation (DUTCH) · SAM:SAH ratio (research)
Clinical Reference — Key Nodes
Cycle Metabolites

The four main players

  • Methionine — essential amino acid from protein; the cycle's entry point from diet
  • SAM — the universal methyl donor; used in 200+ methylation reactions across the body
  • SAH — produced after SAM donates its methyl group; becomes homocysteine
  • Homocysteine — the bifurcation point; must be either remethylated back or cleared via transsulphuration
Key Enzymes

Where variants matter

  • MTHFR — converts folate to active 5-MTHF; C677T and A1298C variants reduce activity 30–70%
  • MTR/MS — remethylates homocysteine back to methionine using B12 and 5-MTHF
  • MTRR — regenerates methionine synthase; variants cause functional B12 deficiency despite normal serum levels
  • COMT — methylates catecholamines and oestrogens; slow COMT accumulates dopamine, adrenaline, oestrogen
  • CBS — diverts homocysteine into transsulphuration; fast CBS depletes methyl groups upstream
Nutrient Cofactors

What the cycle runs on

  • B12 (methylcobalamin) — essential cofactor for MTR; functional deficiency common even when serum B12 is normal
  • Folate (5-MTHF) — the methyl donor for remethylation; synthetic folic acid requires MTHFR to convert first
  • Riboflavin (B2/FAD) — MTHFR cofactor; the most commonly overlooked; stabilises the enzyme
  • Zinc — required for MTHFR activity; depleted by glyphosate chelation and poor diet
  • Magnesium — MAT cofactor; widely deficient; required for ATP-dependent methylation reactions
Downstream Outputs

What methylation produces

  • DNA methylation — gene expression regulation; epigenetic stability; cancer suppressor gene activation
  • Neurotransmitters — serotonin, dopamine, noradrenaline, adrenaline synthesis and metabolism via COMT
  • Creatine — uses ~70% of available methyl groups; fatigue when synthesis is impaired
  • Phospholipids — cell membrane integrity; myelin synthesis; CoQ10 and carnitine production
  • Glutathione — via transsulphuration; the body's master antioxidant and detoxifier
When the Cycle Stalls

Elevated homocysteine consequences

  • Cardiovascular — endothelial damage, thrombotic risk, premature atherosclerosis
  • Neurological — depression, anxiety, cognitive decline, increased dementia risk
  • Reproductive — recurrent miscarriage, neural tube defects, reduced fertility
  • Oestrogen dominance — impaired COMT reduces oestrogen clearance
  • Reduced glutathione — accumulated homocysteine diverted less to transsulphuration
Related Pathways

Connections beyond the core cycle

  • Transsulphuration — homocysteine → cysteine → glutathione via CBS; B6 dependent
  • Oestrogen methylation — COMT converts 2-OHE1 to 2-MeOE1; visible on DUTCH
  • Histamine clearance — HNMT methylates histamine; impaired in poor methylators
  • BH4 pathway — tetrahydrobiopterin production; affects A1298C variant; neurotransmitter synthesis
  • Creatine/phosphocreatine — energy buffer in muscle and brain; biggest consumer of SAM

Testing turns this diagram
into your personal clinical picture.

The diagram shows the pathway. Functional testing shows where your pathway is stalling — homocysteine, OAT markers, DUTCH oestrogen methylation — and makes the intervention specific rather than generic.

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