MTR (5-methyltetrahydrofolate-homocysteine methyltransferase) encodes methionine synthase, a critical enzyme that converts homocysteine to methionine while regenerating tetrahydrofolate. This enzyme requires vitamin B12 as a cofactor and sits at the intersection of folate and B12 metabolism. The A2756G variant affects enzyme function, with implications for homocysteine levels, neural tube defect risk, and overall methylation capacity.
Understanding Methionine Synthase
MTR performs a crucial reaction in the methylation cycle:
- Reaction: Converts homocysteine → methionine
- Methyl donor: 5-methyltetrahydrofolate (5-MTHF)
- Cofactor: Vitamin B12 (methylcobalamin)
- Products: Methionine (for SAM synthesis) + THF (for nucleotide synthesis)
Position in Metabolism
- Links folate cycle to methionine cycle
- Regenerates THF for DNA synthesis
- Provides methionine for S-adenosylmethionine (SAM) production
- Prevents homocysteine accumulation
The A2756G Variant (Asp919Gly)
- A allele: Aspartic acid at position 919 - reference
- G allele: Glycine at position 919 - variant
Understanding Your Genotype
- A/A: Reference genotype - typical enzyme function
- A/G: Heterozygous - may have altered function
- G/G: Homozygous variant - potentially increased enzyme activity or altered B12 handling
Functional Effects
The G allele's effects are somewhat paradoxical:
- Some studies suggest increased enzyme activity
- May consume methyl-B12 more rapidly
- Could lead to functional B12 deficiency despite normal levels
- Effects depend on B12 and folate status
Homocysteine Connection
Why Homocysteine Matters
- Elevated homocysteine is a cardiovascular risk factor
- Associated with stroke, heart disease, cognitive decline
- MTR is one of two pathways for homocysteine disposal
- Other pathway: BHMT (betaine-homocysteine methyltransferase)
MTR and Homocysteine Levels
- Efficient MTR keeps homocysteine low
- G/G genotype may have lower homocysteine if well-nourished
- But increased B12 turnover could raise homocysteine if B12 insufficient
- Context (B12, folate status) determines effect
Vitamin B12 Implications
Increased B12 Need
- G allele may increase methylcobalamin turnover
- May need more B12 to maintain function
- Functional B12 deficiency possible with normal blood levels
- Consider methylmalonic acid (MMA) testing for functional B12 status
B12 Form Considerations
- Methylcobalamin: Active form used directly by MTR
- Adenosylcobalamin: Other active form (mitochondrial)
- Cyanocobalamin: Requires conversion, may be less optimal
- G/G carriers may benefit from methylcobalamin supplementation
Neural Tube Defects
MTR and NTD Risk
- MTR is essential for proper neural tube closure
- Variants affecting MTR may influence NTD risk
- Some studies show G allele associations with spina bifida
- Effects modified by B12 and folate status
Pregnancy Considerations
- Adequate B12 particularly important for G/G carriers
- Folate supplementation standard but B12 often overlooked
- Test B12 levels before and during pregnancy
- Consider methylcobalamin supplementation
Interaction with Other Genes
MTHFR
- MTHFR produces 5-MTHF (MTR's methyl donor)
- MTHFR variants reduce 5-MTHF availability
- MTR + MTHFR variants may have additive effects
- Combined analysis important
MTRR
- MTRR regenerates MTR's B12 cofactor
- MTRR variants impair MTR reactivation
- MTR + MTRR variants compound methylation issues
- See MTRR page for details
CBS
- Alternative pathway for homocysteine (transsulfuration)
- CBS upregulation may compensate for MTR issues
- Complex interactions in methylation network
Supporting MTR Function
Vitamin B12
- Essential cofactor for MTR
- Consider methylcobalamin or adenosylcobalamin forms
- Typical doses: 1000-5000 mcg for supplementation
- Higher doses may be needed for G/G with deficiency
Folate
- Provides 5-MTHF, the methyl donor
- Methylfolate (5-MTHF) preferred over folic acid
- Supports MTR reaction
Testing Recommendations
- Serum B12: Basic screening
- Methylmalonic acid (MMA): Functional B12 status
- Homocysteine: Overall methylation function
- Holotranscobalamin: Active B12 available to cells
Prevalence
- G allele frequency: ~15-25% in most populations
- G/G genotype: ~3-6%
- Population variation: Some differences across ancestries
Testing with NutraHacker
NutraHacker's Complete Mutation Report analyzes MTR along with MTHFR, MTRR, and other methylation genes, providing a comprehensive view of your methylation capacity.
Frequently Asked Questions
Is the G allele good or bad?
It's complicated. The G allele may increase enzyme activity, which sounds good, but it also may consume B12 more rapidly. With adequate B12, G/G individuals may actually have lower homocysteine. But with marginal B12, they could develop functional deficiency faster. The effect depends on your nutritional status - ensure adequate B12 intake.
Should I take methylcobalamin instead of cyanocobalamin?
For MTR variant carriers, methylcobalamin may be theoretically preferable since it's the form MTR actually uses. However, cyanocobalamin is well-converted in most people and has more stability data. Either can work, but if you have G/G genotype and suboptimal B12 status, methylcobalamin provides the ready-to-use form.
How does this relate to MTHFR?
MTR and MTHFR work in sequence. MTHFR produces the methyl donor (5-MTHF) that MTR uses. If you have variants in both genes, methylation capacity may be more significantly affected. Analyzing both together gives a more complete picture of your methylation genetics.
References
- Leclerc D, et al. Molecular biology of methionine synthase: from cofactor recognition to substrate processing. Vitam Horm. 2013;92:113-164.
- Chen J, et al. A polymorphism in the methionine synthase gene and the risk of neural tube defects. Am J Epidemiol. 2000;152(12):1192-1196.
- Gaughan DJ, et al. The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis. 2001;157(2):451-456.