One Carbon Metabolism

The biochemical system providing the universal methyl donor for all epigenetic methylation reactions. Substrate starvation of this cycle is the primary epigenetic failure mode in this clinical context.

The Cycle

Dietary folate → 5,10-methyleneTHF  [MTHFR, requires B2, zinc]
                       ↓
                 5-MTHF (methylfolate)
                       ↓ + homocysteine
                 Methionine             [methionine synthase, requires B12]
                       ↓ + ATP
                   SAM                 [MAT enzyme, requires Mg²⁺]
                       ↓ (methyl group donated to DNA, histones, RNA, lipids)
                   SAH
                       ↓
                 Homocysteine          [must clear efficiently]
                    ↙    ↘
         Remethylation   Transsulfuration
        (back to Met)    Cystathionine [B6]
                              ↓        [B6]
                           Cysteine
                              ↓
                         Glutathione

SAM — The Universal Methyl Donor

Every methylation reaction in the body uses SAM:

• DNA methyltransferases (DNMT1, DNMT3A, DNMT3B): CpG methylation
• Histone methyltransferases (EZH2, G9a, SUV39H1): histone methylation marks
• RNA methyltransferases: mRNA cap methylation
• Phosphatidylcholine synthesis: membrane composition
• Neurotransmitter methylation: epinephrine, melatonin synthesis
• Creatine synthesis: muscle energy

If SAM is depleted, all of these fail simultaneously. The clinical presentation of SAM deficiency is therefore heterogeneous — affects every system that uses methylation.

Rate-Limiting Nutrients

Nutrient	Role	Common status in this context
5-MTHF (methylfolate)	One-carbon unit donor to homocysteine	Depleted by gut dysbiosis (microbial B9 production reduced); MTHFR polymorphisms (40–60% of relevant population reduce MTHFR efficiency 30–70%)
Methylcobalamin (B12)	Methionine synthase cofactor	Depleted by gut dysbiosis; metformin; PPIs
Riboflavin (B2)	MTHFR enzyme function	Commonly low; MTHFR polymorphisms worsen
Zinc	MTHFR cofactor, methionine synthase	Depleted by chronic inflammation
Magnesium	ATP-Mg²⁺ for MAT enzymes	Broadly deficient in modern diets
Methionine	Substrate	From protein — meat, eggs, fish
Betaine/TMG	Alternative methyl donor via BHMT	From beets, spinach, wheat germ
Choline	Betaine precursor	From egg yolk, liver

MTHFR Polymorphisms

MTHFR C677T and A1298C are common variants that reduce enzyme efficiency:

• Homozygous C677T: ~70% reduction in MTHFR activity
• Compound heterozygous: ~50–60% reduction
• Prevalence: ~40–60% of people have at least one copy of C677T

The clinical implication: these individuals cannot efficiently convert dietary folate to 5-MTHF, making supplemental methylfolate (5-MTHF) rather than folic acid essential for maintaining the SAM cycle.

Elevated homocysteine is the diagnostic indicator that the cycle is impaired. Target homocysteine: <7 μmol/L for optimal methylation function.

The Alternative Pathway — BHMT

Betaine:homocysteine methyltransferase (BHMT) operates in the liver independently of MTHFR:

Betaine + Homocysteine → Methionine + Dimethylglycine

This alternative pathway:

• Bypasses the MTHFR step entirely
• Is specific to liver (not active in other tissues)
• Requires betaine (from beets, spinach, wheat germ, or TMG supplement)
• Provides a meaningful bypass for MTHFR-impaired individuals

The Transsulfuration Output — Glutathione

The transsulfuration pathway converts homocysteine → cystathionine → cysteine → glutathione. This means:

1. The methylation cycle and the antioxidant defense system share a common substrate (homocysteine)
2. High methylation demand can compete with glutathione synthesis for homocysteine
3. High oxidative stress depletes glutathione → homocysteine accumulates → homocysteine-mediated vascular and epigenetic damage
4. NAC supplementation provides cysteine downstream of the homocysteine branch point — it feeds glutathione synthesis without competing with the methylation cycle for homocysteine

This is the mechanistic reason why NAC + betaine/TMG together address both the antioxidant and epigenetic substrate deficits more effectively than either alone.

Connections

• [[Epigenetic Transmission]] — what this cycle enables
• [[Phase 0 - Source Control and Redox]] — glutathione connection
• [[Phase 3 - Epigenetic Reprogramming]] — where these substrates are used
• [[NAD Pool]] — parallel epigenetic substrate system
• [[TET Enzymes]] — what active demethylation requires
• [[Quorum Sensing]] — bacterial SAM cycle produces AI-2