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.
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 to the molecule.
The methylation cycle is your body’s way of recycling 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 methylation reactions.[ref]
Examples of methylation reactions include:
- synthesis of some of the nucleic acid (DNA) bases
- turning off genes so that they aren’t transcribed (DNA methylation)
- converting serotonin into melatonin
- methylating arsenic so that it can be excreted
- breaking down neurotransmitters
- metabolizing estrogen
- regenerating methionine from homocysteine
Methylation in the right amount:
Goldilocks comes to mind here… You want to have the right amount of methylation reactions going on. Your cells work to keep this all in balance.
For example, you need enough folate (vitamin B9) and methylcobalamin (vitamin B12) for the methionine synthase reaction to occur. Methylfolate 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 strongly associated with increased risk of heart disease.[ref]
The other side of the picture, though, is that there may be times when 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.
MTR and MTRR Genotype Report:
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 (MTRR) encodes the 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 that 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 —.
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Ankar, Alex, and Anil Kumar. “Vitamin B12 Deficiency.” StatPearls, StatPearls Publishing, 2022. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK441923/.
Deng, Changfei, et al. “Genetic Polymorphisms in MTR Are Associated with Non-Syndromic Congenital Heart Disease from a Family-Based Case-Control Study in the Chinese Population.” Scientific Reports, vol. 9, no. 1, Mar. 2019, p. 5065. PubMed, https://doi.org/10.1038/s41598-019-41641-z.
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Luo, Mei, et al. “Correlation of Homocysteine Metabolic Enzymes Gene Polymorphism and Mild Cognitive Impairment in the Xinjiang Uygur Population.” Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, vol. 21, Jan. 2015, pp. 326–32. PubMed Central, https://doi.org/10.12659/MSM.893226.
“Methionine Synthase.” Wikipedia, 30 Sept. 2022. Wikipedia, https://en.wikipedia.org/w/index.php?title=Methionine_synthase&oldid=1113220848.
Pardini, Barbara, et al. “MTHFR and MTRR Genotype and Haplotype Analysis and Colorectal Cancer Susceptibility in a Case-Control Study from the Czech Republic.” Mutation Research, vol. 721, no. 1, Mar. 2011, pp. 74–80. PubMed, https://doi.org/10.1016/j.mrgentox.2010.12.008.
Raffield, Laura M., et al. “Genome-Wide Association Study of Homocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Coronary Artery Risk in Young Adults Study.” Journal of Human Genetics, vol. 63, no. 3, Mar. 2018, pp. 327–37. PubMed Central, https://doi.org/10.1038/s10038-017-0384-9.
Roffman, Joshua L., et al. “Genetic Variation Throughout the Folate Metabolic Pathway Influences Negative Symptom Severity in Schizophrenia.” Schizophrenia Bulletin, vol. 39, no. 2, Mar. 2013, pp. 330–38. PubMed Central, https://doi.org/10.1093/schbul/sbr150.
Sangrajrang, Suleeporn, et al. “Genetic Polymorphisms in Folate and Alcohol Metabolism and Breast Cancer Risk: A Case-Control Study in Thai Women.” Breast Cancer Research and Treatment, vol. 123, no. 3, Oct. 2010, pp. 885–93. PubMed, https://doi.org/10.1007/s10549-010-0804-4.
Wang, Ping, et al. “Association of MTRR A66G Polymorphism with Cancer Susceptibility: Evidence from 85 Studies.” Journal of Cancer, vol. 8, no. 2, 2017, pp. 266–77. PubMed, https://doi.org/10.7150/jca.17379.
Weiner, Alexandra S., et al. “Methylenetetrahydrofolate Reductase C677T and Methionine Synthase A2756G Polymorphisms Influence on Leukocyte Genomic DNA Methylation Level.” Gene, vol. 533, no. 1, Jan. 2014, pp. 168–72. PubMed, https://doi.org/10.1016/j.gene.2013.09.098.
Xu, Weihai, et al. “Association between Methionine Synthase Reductase A66G Polymorphism and Male Infertility: A Meta-Analysis.” Critical Reviews in Eukaryotic Gene Expression, vol. 27, no. 1, 2017, pp. 37–46. PubMed, https://doi.org/10.1615/CritRevEukaryotGeneExpr.2017018680.