MTR A2756G

MTR — The Methionine Synthase

Methionine synthase (MTR), also known as MS, catalyzes the final step that
converts homocysteine back to methionine using methylcobalamin (active B12) as
a cofactor and methylfolate as the methyl donor. This reaction sits at the
crossroads of the methylation cycle and is essential for keeping homocysteine
levels in check.

The Mechanism

The A2756G variant (rs1805087) causes an aspartic acid-to-glycine substitution | Aspartic acid-to-glycine substitution at position 919 of the protein (p.Asp919Gly)
at position 919 of the MTR protein. The G allele produces an enzyme with altered
activity that tends to favor the active (reduced) state of B12. Paradoxically,
this may seem beneficial, but the altered enzyme kinetics can lead to disrupted
methylation cycling under certain conditions, particularly when B12 or folate
levels are suboptimal. ClinVar classifies this variant as benign given its
population frequency.

The Folate Trap

MTR is at the center of what biochemists call the "methyl-folate trap." | When MTR is impaired, methylfolate accumulates unusably — a functional folate deficiency despite normal blood levels When MTR
activity is impaired, methylfolate accumulates because it cannot donate its methyl
group to homocysteine. This creates a functional folate deficiency even when total
folate levels appear adequate. Understanding your MTR status helps explain why
some people with "normal" folate levels still show signs of impaired methylation.

Clinical Significance

Studies have linked the G allele to altered homocysteine metabolism, though the
effects are typically modest. A meta-analysis | Zhao D et al. MTR A2756G and cancer risk, 2010 examined the variant's
association with cancer risk across multiple study types. The variant becomes more
clinically relevant when combined with MTRR variants (which affect B12 reactivation)
and MTHFR variants (which affect methylfolate production). This triad of enzymes
works as a coordinated system | MTR + MTRR + MTHFR form a triad: folate provides the methyl group, B12 carries it, and MTRR keeps B12 active, and weakness at multiple points compounds the effect.

Practical Implications

If you carry the G allele, ensuring generous B12 intake is important since your
MTR enzyme has altered B12 handling. Active B12 forms are preferred. Combined
with adequate folate (as methylfolate if you have MTHFR variants), this supports
optimal homocysteine conversion and methylation cycling.

Interactions

MTR works directly with MTRR (rs1801394) — MTR performs the reaction and MTRR
reactivates it. Both interact with MTHFR (rs1801133) as the provider of the
methylfolate substrate.