MTR and MTRR Genes: Methylation cycle and the need for Vitamin B12

The MTR (methionine synthase) gene and the MTRR (methionine synthase reductase) gene both code for enzymes that are involved in the conversion of homocysteine to methionine. They are essential players in the methylation cycle.

This article explains where the MTR and MTRR genes fit within the methylation cycle. I’ll show you how to check your 23andMe or AncestryDNA raw data for the MTR and MTRR SNPs, and then explain how to optimize your diet for these variants.

MTR & MTRR Gene:  Methionine and Vitamin B12

Methionine is an essential amino acid, used in the production of proteins. It is literally the starting amino acid for every protein your body makes.

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

MTR (methionine synthase) and MTRR (methionine synthase reductase) code for two enzymes that work together in the methylation cycle.

  • The MTR gene works in the final step to regenerate homocysteine into methionine using methyl-B12 (methylcobalamin)
  • MTRR regenerates the methylcobalamin for MTR to use again. [ref]

Both are a vital part of the methylation cycle.

Methyl groups – in a nutshell:

Your body is made up of a bunch of organic molecules, a lot of which contain carbons bonded to hydrogen. Adding in a methyl group (one carbon plus three hydrogens) is like adding a building block onto the molecule.

The methylation cycle is your body’s way of cycling certain molecules to ensure that there are enough methyl groups (carbon plus three hydrogens) available for cellular processes. When it comes to the functioning of your cells, methyl groups are used in a bunch of ways.[ref]

Examples of methylation reactions include:

  • synthesis of some of the nucleic acid (DNA) bases
  • turning off genes so that they aren’t transcribed
  • converting serotonin into melatonin
  • methylating arsenic so that it can be excreted
  • regenerating methionine from homocysteine

Methylation in the right amount:

Goldilocks comes to mind here… You want to have the ‘just right’ amount of methylation reactions going on. Your cells work to keep this all in balance.

For example, you need enough folate and methylcobalamin for the methionine synthase reaction to occur. Methyl folate is the source of the methyl group that methionine synthase uses for converting homocysteine to methionine.  (Read more about your MTHFR genes and methyl folate)

Not enough B12 or methyl folate? MTR won’t convert as much homocysteine to methionine, leading to a buildup of homocysteine and limiting methionine. Too much homocysteine is associated with an increase in the risk of heart disease.[ref]

The other side of the picture, though, is that there may be times that limiting methionine is helpful, such as in fighting the proliferation of cancer cells.  Methotrexate, a chemotherapy drug, works by inhibiting the production of methyl folate, thus limiting methionine and DNA synthesis for cell growth.

Genetic Variants in the MTR and MTRR genes:

Differences in the MTR and MTRR genes can impact your overall wellness.

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MTR Genetic Variants:

Check your genetic data for rs1805087 A2756G (23andMe v4, v5; AncestryDNA):

  • A/A: typical
  • A/G: increased enzyme activity, increased severity of schizophrenia
  • G/G: increased enzyme activity [ref] increased severity of schizophrenia [ref] increased risk of cognitive impairment (likely due to higher homocysteine) [ref]

Members: Your genotype for rs1805087 is .

Check your genetic data for rs1050993 (AncestryDNA):

  • A/A: increased risk of breast cancer[ref]; increased risk of congenital heart disease[ref]
  • A/G: typical risk of breast cancer, increased risk of congenital heart disease
  • G/G: typical

Members: Your genotype for rs1050993 is .

Check your genetic data for rs2275565 (23andMe v4, v5; AncestryDNA):

  • T/T: linked with higher homocysteine levels [ref] likely higher enzyme activity levels
  • G/T: linked with higher homocysteine levels
  • G/G: typical

Members: Your genotype for rs2275565 is .

MTRR Genetic Variants:

Methionine synthase reductase has several fairly common variants that affect the production of the MTRR enzyme which regenerates vitamin B12 (methylcobalamin) for use by MTR and other enzymes. The variant rs1801394 (below) is also known as A66G, and it decreases this enzyme’s efficiency.  It is a fairly common variant which is carried by about half the population. It seems that combinations of MTRR polymorphisms with MTHFR or other methylation cycle issues may be more of a concern than just carrying the single MTRR variant.

Check your genetic data for rs1801394 A66G (23andMe v4, v5; AncestryDNA):

  • A/A: typical
  • A/G: somewhat decreased enzyme efficiency; increased risk for male infertility, slightly increased risk for cancer; increased risk for colon cancer; increased risk for congenital heart disease
  • G/G: decreased enzyme efficiency; increased risk for male infertility, slightly increased risk for cancer; increased risk for colon cancer; increased risk for congenital heart disease [ref][ref][ref][ref][ref]

Members: Your genotype for rs1801394 is .



Zinc: MTR uses methylB12 (methylcobalamin) and zinc as cofactors in the reaction of converting homocysteine to methionine.  Thus, an increase in enzyme activity (e.g. rs1805087) could keep homocysteine levels lower (generally a good thing), but only if there is plenty of methylcobalamin (B12). So people with this variant should ensure that they are getting  methyl-B12 and zinc, either through diet or supplements.

Folate and B12: 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
  • legumes

Vitamin B12 is only found in animal products with liver being an excellent source.

Caution on MethylB12: If you have the MTRR polymorphisms and are considering supplementing with B-12, you should first read this article on COMT.  There are four different types of B-12, and some work better than others, depending on your COMT variants.

Related Genes and Topics:

Folate & MTHFR
The MTHFR gene codes for a key enzyme in the folate cycle. MTHFR variants can decrease the conversion to methyl folate.

CBS variants and low sulfur
This article digs into the high quality research on the common CBS genetic variants to determine if there is any evidence suggesting everyone should be on a low-sulfur diet. Read through the research and check your genetic data.

Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.