Methylation: Folate, B12, SAMe & the Methylation Cycle Explained

Methylation is one of the most fundamental biochemical processes in the body — the transfer of a one-carbon methyl group (CH3) from a donor molecule to a recipient. This simple reaction is involved in DNA regulation (gene silencing), neurotransmitter synthesis and metabolism, detoxification (phase II), creatine and phospholipid synthesis, and homocysteine recycling.

The Methylation Cycle

The core of the methylation cycle converts homocysteine back to methionine, which is then activated to S-adenosylmethionine (SAMe) — the body's universal methyl donor. SAMe donates its methyl group and becomes S-adenosylhomocysteine (SAH), then homocysteine, completing the cycle. This cycle requires folate (B9) as 5-MTHF, vitamin B12 (as methylcobalamin), and is supported by B6, B2, and betaine (trimethylglycine).

When Methylation Is Impaired

MTHFR gene variants reduce the production of 5-MTHF from folic acid. B12 deficiency prevents homocysteine from being recycled to methionine. The result: homocysteine accumulates (a cardiovascular risk marker), SAMe production drops (affecting neurotransmitter balance, detoxification capacity, and gene regulation), and the entire cycle slows down.

Glycine is relevant here because SAMe is the primary methyl donor for glycine N-methyltransferase, and creatine synthesis (which uses SAMe) consumes more methyl groups than any other process in the body.