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.
Strong evidence · Last reviewed:
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
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 in the knowledge graph
Biomarkers
Homocysteine — Homocysteine accumulates when methylation cycle activity is impaired. Strong evidence
Genes
MTHFR — MTHFR is the rate-limiting enzyme of the methylation cycle. Strong evidence
COMT — COMT uses SAMe (the methylation cycle's output) to clear catecholamines. Strong evidence
Supplements
L-Methylfolate — 5-MTHF directly supplies the methyl-donating step of the cycle. Strong evidence
FAQ
What raises homocysteine?
Low folate, B12 or B6; MTHFR variants combined with low folate intake; renal impairment; hypothyroidism; heavy alcohol use; certain medications.
Do I need to 'support methylation' if I have MTHFR?
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.
References
Selhub, J Nutr Health Aging 2002 — PMID 11960325. Folate, B12 and B6 status are primary modifiable determinants of homocysteine.