MTR / MTRR – Homocysteine, methionine, and B12

Methionine is an essential amino acid that plays an integral part in the methylation pathway. S-adenosyl methionine (SAMe) is a derivative of methionine and is involved in many cellular pathways as a methyl donor.

Methionine synthase (MTR) - image from Wikimedia Commons
Methionine synthase (MTR) – image from Wikimedia Commons

MTR (methionine synthase) and MTRR (methionine synthase reductase) code for enzymes work together in the methylation cycle. MTR works in the final step to regenerate homocysteine into methionine using methylcobalamin (methyl-B12), and MTRR regenerates the methylcobalamin for MTR to use. [ref]  Both are a vital part of the methylation cycle.

The Genetics Home Reference sums it up this way: “The MTR gene provides instructions for making an enzyme called methionine synthase. This enzyme plays a role in processing amino acids, the building blocks of proteins. Specifically, methionine synthase carries out a chemical reaction that converts the amino acid homocysteine to another amino acid called methionine. The body uses methionine to make proteins and other important compounds. To function properly, methionine synthase requires methylcobalamin (a form of vitamin B12) and another enzyme called methionine synthase reductase, which is produced from the MTRR gene.”

MTR Polymorphisms:

Studies have linked an MTR variant to several folate pathway problems including higher homocysteine levels.  The rs1805087 is also known as A2756G, with G being the minor allele.  A 2014 study showed that those with the homozygous polymorphism (GG) had higher DNA methylation than those with the wildtype (AA). [ref]

Here are several recent studies on this MTR polymorphism:

  • A 2015 study showed that rs1805087 is a risk factor for mild cognitive impairment (Chinese study).  The study notes that high homocysteine levels are a risk factor for decline in cognitive function in the elderly. [ref]
  • A 2015 study found that adhering to the Mediterranean diet reduced the risk of breast cancer for those with the MTR polymorphism.  [ref]
  • Quite a few recents studies found no association between the MTR polymorphism and cancer risks.
  • A 2013 study showed that rs1805087 increased the severity of symptoms in schizophrenia. [ref]
  • A small Iranian study found that the MTR A2756G variant was linked to a slightly higher risk of autism.
Check your 23andMe results for rs1805087:

  • AA: normal (wildtype)
  • GG: increased DNA methylation

MTRR Polymorphisms:

Methionine synthase reductase has several fairly common polymorphisms that affect the production of the MTRR enzyme which regenerates vitamin B12 (methylcobalamin).  The variant rs1801394 is also known as A66G, and it decreases enzyme’s efficiency.   Note that the increased risk of most of the studies is not all that large, and it seems that combinations of MTRR polymorphisms with MTHFR or other methylation cycle issues may be more of a concern.

  • A 2011 study showed an increased risk for colorectal cancer (OR = 1.39) for those with rs1801394  GG. [ref]
  • A 2014 study showed an increased risk for metabolic syndrome for those with the A66G polymorphisms and MTHFR C677T.  [ref]
  • A 2014 meta-analysis showed an increased risk for congenital heart disease associated with A66G polymorphism.  [ref]
Check your 23andMe results for rs1801394:

  • AA: normal (wildtype)
  • AG: somewhat decreased enzyme efficiency
  • GG: decreased enzyme efficiency

Diet and Supplements:

  • A healthy diet high in folate and B12 seems to be essential for overcoming any deficits created by these two polymorphisms.  Foods high in folate include leafy greens, chicken liver, beef liver, asparagus, broccoli, and legumes.  Vitamin B12 is only found in animal products with liver being an excellent source.
  • If you have the MTRR polymorphisms and are considering supplementing with B-12, you should first read through the article on COMT.  There are four different types of B-12, and some work better than others, depending on COMT polymorphisms.
  • If you are looking for a good adenosylcobalamin and hydroxocobalamin sublingual supplement, I like the Seeking Health brand combo Hydrox-Adeno.  There are many good sources of methylcobalamin, and you may be able to find it at your local health food store as well.


Updated 5/2017

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