5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase


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5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase (MTRR) is an enzyme which interacts with methionine synthase, to ensure the continued production of the essential amino acid methionine, and is encoded for by the MTRR gene 1.

Methionine is an essential amino acid and is required for numerous processes throughout the body. A major source of methionine is the enzyme methionine synthase which converts homocysteine into methionine, using 5-methlytetrahydrofolate (MTHF) produced by methylenetetrahydrofolate reductase (MTHFR) as a methyl donor 2.

The activity of methionine synthase requires vitamin B12 as a co-factor, however over time this becomes inactivated. MTRR breaks the association between methionine synthase and inactive vitamin B12, allowing a new functional vitamin B12 molecule to bind, ensuring continuing production of methionine 3.

There is one SNP in MTRR associated with poor health outcomes, rs1801394 or A66G.


Gastrointestinal Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs1801394 a g 47IleMet

Risk Description

The risk ‘G’ allele of A66G in the MTRR gene is associated with an accumulation of homocysteine 4, which is in turn associated with a variety of disorders including cancers, heart disease, stroke, raised blood pressure and potential issues with birth defects 57.

MTRR is responsible for breaking methionine synthase and its vitamin B12 co-factor apart, when the co-factor becomes inactivated over time. The risk ‘G’ allele of A66G has been shown to interact less strongly with methionine synthase leading to reduced activity, and eventually an accumulation of homocysteine 8.

Indirect Nutrients:*

IngredientActive IngredientEffect
Vitamin B12 Methylcobalamin

Vitamin B12 is the cofactor for methionine synthase. When bound methionine synthase can process homocysteine into the essential amino acid methionine. Over time the vitamin B12 molecule loses its effectiveness and must be removed, and replaced with a new molecule, which is achieved by MTRR 8.

The risk ‘G’ allele of A66G is associated with a reduction in its activity. Whilst supplementation with vitamin B12 will not benefit MTRR activity directly it may help ensure maximal methionine sythnase function.


Methionine synthase converts homocysteine into the essential amino acid methionine. The risk ‘G’ allele of A66G in the MTRR gene leads to reduced methionine synthase activity. This can promote homocysteine accumulation, but can also limit the availability of methionine. Supplementation with L-methionine can ensure that an appropriate supply of methionine is available for cells and tissues.

Nutritional Contraindications:*

IngredientActive IngredientEffect
Alcohol Acetaldehyde

Acetaldehyde is required by the body in small amounts, yet is toxic when present at high levels, indeed AH is the breakdown product of ethanol responsible for many of the symptoms associated with hangovers 9.

One of the mechanisms by which acetaldehyde induces its toxicity is by inhibiting the enzyme methionine synthase 100. Methionine synthase activity is reduced in those carrying the risk ‘G’ allele of A66G in the MTRR gene. Therefore carriers may benefit from avoiding generation of excessive acetaldehyde.

Discuss this information with your doctor before taking any course of action.



  1. Beverley Dubus says:


    My child has polymorphisms MTHFR, MTRR, is low in methionine, low SAM, high homocysteine. Does will with B12 methylcobalamin but cannot tollerate supplementation with L-methionine or SAM-e. If he eats protein whilst taking these..he is very sick. Any thoughts?

  2. DW says:


    Supplementing with B12 has been a help for me. I wonder about taking l-methionine. Some experts say that if your body is able to make homocysteine from methionine but is less effective at converting homocysteine back to methionine – then taking l-methionine will increase your homocysteine levels even more. Also, I’ve read studies in which rats were fed methionine chow in order to increase their homocysteine levels. I would wonder if it would be better to simply support the long conversion route with B12 (as you’ve recommended) and possibly support the short conversion route (BHMT) with TMG (if necessary) – but not take l-methionine supplements. Thoughts?

    • Kathy says:

      SNP: MTRR rs1801394

      I have recently been confirmed with the MTRR rs1801394 gene as well as the FUT2 (Vitamin B12) from the DNA test performed by Uforia Science. The best thing is that Uforia will also customize a supplement for you based on your DNA results, so now I now longer have to guess how much B12 or l-methionine to take because they’ve done all the research for me and they make it from plant based nutrients all Non-GMO, organic, gluten free and vegan. I can share the website information if you are interested.

      • Andrea says:

        Hi Kathy –
        I would be interested in the website, thanks! I have the MTRR rs1801394 gene as well, I’m vegan (so I already struggle with B12 sources). There’s so much information out there, it’s hard to know what to do/follow. Thanks in advance for the link!

      • Chris says:

        I would be wary of this Uforia, seems to be MLM company. Based on current science, it is very difficult to come up with an effective supplementation plan without a lot of research, blood tests (not just genetic tests) etc.

      • Marion E Painter says:

        That’s fantastic! I was just thinking yesterday that the future of all of this research is to have customizable supplements based on our DNA results! Great to know it’s already happening. Thanks for that info as I have this gene as well.

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