# The Methylation Cycle
URL: https://genohealth.app/pathways/methylation-cycle
Type: Pathway
Evidence: Strong evidence
Last reviewed: 2025-06-30

## Intro
Methylation is the chemistry of transferring methyl groups (CH3) onto DNA, neurotransmitters, hormones and toxins. The cycle runs on folate, B12, B6, riboflavin, choline and SAMe — and the MTHFR enzyme is the rate-limiting step that converts folate into its active form.

## Summary
The biochemical cycle that recycles homocysteine, builds neurotransmitters and methylates DNA — and the reason MTHFR, B12 and folate get so much attention.

## Key facts
- Rate-limiting enzyme: MTHFR (C677T, A1298C)
- Output marker: SAMe : SAH ratio; homocysteine
- Key nutrients: Folate, B12, B6, riboflavin, choline

## How the cycle works (simplified)
- Folate is converted to 5-MTHF by the MTHFR enzyme
- 5-MTHF donates a methyl group to homocysteine, regenerating methionine
- Methionine becomes SAMe — the universal methyl donor
- SAMe donates methyl groups to DNA, neurotransmitters, hormones and toxins, becoming SAH
- SAH is recycled back to homocysteine, and the cycle continues

## Why it matters
- Inefficient methylation raises homocysteine — a cardiovascular and cognitive risk marker
- Methylation regulates gene expression (DNA methylation patterns)
- Builds and recycles neurotransmitters (dopamine, serotonin, norepinephrine)
- Detoxifies estrogen metabolites, histamine and certain drugs

## Levers that support it
- Adequate folate (food first; 5-MTHF or folinic acid for MTHFR carriers)
- B12 — hydroxocobalamin for methyl-sensitive users
- B6 (P-5-P), riboflavin (B2) — cofactors for the cycle
- Choline / phosphatidylcholine — alternative methyl pathway
- Limit alcohol — depletes folate and B-vitamins

## Related (knowledge graph)

### Biomarkers
- Homocysteine (/biomarkers/homocysteine): Homocysteine accumulates when methylation cycle activity is impaired. [Strong evidence]

### Genes
- MTHFR (/genes/mthfr): MTHFR is the rate-limiting enzyme of the methylation cycle. [Strong evidence]
- COMT (/genes/comt): COMT uses SAMe (the methylation cycle's output) to clear catecholamines. [Strong evidence]

### Supplements
- L-Methylfolate (/supplements/methylfolate): 5-MTHF directly supplies the methyl-donating step of the cycle. [Strong evidence]

## FAQ
**Q: What raises homocysteine?**
A: Low folate, B12 or B6; MTHFR variants combined with low folate intake; renal impairment; hypothyroidism; heavy alcohol use; certain medications.

**Q: Do I need to 'support methylation' if I have MTHFR?**
A: Most MTHFR heterozygotes do fine on a folate-rich diet. Homozygotes — especially with elevated homocysteine — benefit from active folate (5-MTHF or folinic acid) plus B12.

## Citations
- Selhub, J Nutr Health Aging 2002 (PMID 11960325): Folate, B12 and B6 status are primary modifiable determinants of homocysteine.

Disclaimer: Informational only — not medical advice.