Summary

MTR A2756G affects the enzyme that actually performs the homocysteine-to-methionine conversion — the reaction that MTHFR and MTRR both feed into. The G allele alters how the enzyme holds onto its B12 cofactor, creating a subtle shift in methylation flux that matters most when stacked with other methylation variants.

Genotype spectrum

AA (Wild type)

Standard methionine synthase function. Your enzyme holds onto B12 efficiently.

AG (Heterozygous)

Minimal standalone impact. You're in the moderate group where this is usually clinically silent.

GG (Homozygous)

Rare genotype — if you carry it, you have a specific, well-defined bottleneck in B12 utilisation that interventions can target directly.

Practical takeaway

For GG Carriers (Moderate Attention)
• Methylcobalamin: 1000-2000 mcg/day sublingual. Your enzyme burns through B12 faster — keep the supply high.
• Riboflavin (B2): 1.6 mg/day. Supports MTRR function (which your MTR depends on more heavily than average).
• Test: Serum B12 + MMA + homocysteine. MMA is especially important — it reflects intracellular B12 status, which is what matters for MTR function.
• If stacked with MTRR GG: Full methylation protocol. This is the double-hit scenario on the same reaction. B12 is your priority intervention.
For AG Carriers (Low Priority Alone)
• Standard B12 adequacy. Methylcobalamin is a reasonable default form.
• Becomes clinically relevant only in compound with MTHFR or MTRR variants.
For AA Carriers (No Action)
• Normal MTR function. Standard dietary guidance.

Evidence detail

What This Gene Does

MTR (methionine synthase) is the workhorse enzyme at the centre of the methionine cycle. It takes homocysteine and converts it to methionine using methylfolate as the methyl donor and methylcobalamin (B12) as the cofactor. This is THE reaction that clears homocysteine and produces methionine for SAM synthesis. MTHFR makes the methylfolate, MTRR maintains the B12 — but MTR is the enzyme that actually performs the conversion.

The A2756G variant (Asp919Gly) sits near the B12-binding domain. The G allele produces an enzyme with altered B12 binding kinetics — it turns over methylcobalamin faster, which paradoxically means it needs more frequent reactivation by MTRR.

Mechanism

MTR performs the methionine cycle's central reaction:

Homocysteine + 5-methylTHF → Methionine + THF (requires methylcobalamin)

The A2756G variant changes aspartic acid to glycine at position 919, near the cobalamin-binding region. Here's what this does:

1. The G allele enzyme turns over B12 faster. It doesn't "break" the enzyme — it changes the kinetics. The methylcobalamin cofactor gets oxidised more frequently, requiring more MTRR reactivation cycles.

2. When B12 is abundant: The faster turnover may actually increase methylation flux — more frequent reaction cycles, more homocysteine cleared per unit time. This explains why some studies find LOWER homocysteine in GG carriers with good B12 status.

3. When B12 is marginal: The faster oxidation overwhelms MTRR's capacity to regenerate the cofactor. MTR spends more time inactive. Homocysteine accumulates. This explains the B12-conditional effect seen in population studies.

4. The MTRR interaction: If MTRR is also compromised (A66G GG), the MTR enzyme's faster B12 oxidation meets slower B12 regeneration. This is the tightest compound bottleneck in the methylation pathway — enzyme AND maintenance both impaired at the same reaction.

Think of it as: MTR with the G allele is like a car that burns through oil faster. With a good mechanic (efficient MTRR) and plenty of oil (adequate B12), it runs fine. With a slow mechanic (MTRR GG) or low oil (poor B12 intake), it starts to seize up.

MTR A2756G

Summary

Genotype spectrum

Practical takeaway

Evidence detail

Sources (9)