MTR and MTRR: the B12 side of methylation
For anyone ready to understand the genes right next door to MTHFR.
Here’s a handoff that explains a lot about why “just MTHFR” is never the whole story. MTHFR makes your active folate — and then it hands it off. The genes that catch that handoff and actually finish the job are MTR and MTRR, and they run on vitamin B12. If MTHFR is the folate step, MTR and MTRR are the B12 step right beside it.
MTR: the main event
MTR stands for methionine synthase. Its job is the central reaction of this whole cycle: it takes homocysteine (a molecule you want to keep recycling) and, using active B12 and your active folate together, converts it back into methionine — which the body turns into SAMe, the universal methyl donor.
In other words, MTR is where folate and B12 meet to keep methylation running. It’s arguably the step MTHFR exists to supply.
MTRR: the pit crew
Here’s the catch: the B12 that MTR relies on gets “used up” into an inactive state and has to be re-activated to keep working. That’s MTRR — methionine synthase reductase — the pit crew that regenerates MTR’s B12 so the main reaction can keep going.
When people talk about needing more B12 (or specific B12 forms) alongside MTHFR, MTRR is very often the reason underneath it.
The common variant: A66G (rs1801394)
The most-discussed MTRR variant is A66G (also written rs1801394). Like the MTHFR variants, it can modestly influence how efficiently this B12-recycling step runs. And like every variant on this site, it’s common and it’s not a diagnosis — it’s a small dial, most meaningful in context.
Why this matters for you
- B12 forms and status become relevant. If the MTR/MTRR step is a little sluggish, giving the body active B12 (methylcobalamin, adenosylcobalamin) is a sensible, low-drama choice — see nutrient forms that matter.
- It’s why MTHFR alone confuses people. You can have a “fine” MTHFR result and still have questions that only make sense once you look one step downstream, at the B12 side.
The honest caveat
MTR and MTRR are two more instruments in the orchestra — not soloists. Reading them in isolation is just as incomplete as reading MTHFR alone. The value is in seeing the whole set together: the genes that work alongside MTHFR, and ultimately your own full picture.
Education, not medical advice. Genes are dials, not destiny. A qualified practitioner reads them alongside your labs and history — that’s where they become useful.