MTHFR

Protein:

Methylene tetrahydrofolate reductase (MTHFR)

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MTHFR is an enzyme which is encoded by the MTHFR gene and functions to convert 5,10-methylenetetrahydrofolate (MeTHF) to 5-methlytetrahydrofolate (MTHF). Proper MTHFR activity is fundamental to overall good health, as it is responsible for metabolizing dietary folate and folic acid into a variety of other products vital to the synthesis of DNA, RNA and other amino acids 1.

MTHFR forms part of the one carbon pathway which is responsible for converting folate and folic acid into a variety of precursor products which are used to synthesise new DNA, RNA and other amino acids; process which are vital for the cell maintenance and also the production of new, healthy cells 1.

The one carbon pathway also interfaces with the methionine cycle which functions to convert homocysteine into methionine. MTHF, the product produced by MTHFR activity, is used by the enzyme methionine synthase as a methyl donor to convert homocysteine into methionine. As MTHF loses its methyl group tetrahydrafolate (THF) is formed which re-enters the one carbon cycle.

Taken together these pathways are sometimes referred to as the “methylation cycle”. A major activity of the methylation cycle is the transfer of methyl groups between molecules, for example from MTHF to homocysteine, producing methionine and THF.

Reduced MTHFR function leads to one carbon pathway activity stalling, this reduction in activity has numerous effects, two of which are potentially detrimental to health. Firstly, with impaired function molecules which are normally processed by MTHFR can begin to accumulate, this includes MeTHF but also molecules further upstream such as folate. Secondly, with a reduced amount of MTHF being produced the methionine cycle is also slowed, this can lead to the accumulation of homocysteine which has been linked with a variety of disorders including cancers, heart disease, stroke, raised blood pressure and potential issues with birth defects 35.

There are three common SNPs associated with altered MTHFR activity rs1801133 or C667T, rs1801131 or A1289C and rs2066470 or C117T.

C667T

Science Score
Heart Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs1801133 c t 30AlaVal

Risk Description

The risk ‘T’ allele of C667T leads to the production of a heat-sensitive MTHFR enzyme which also displays reduced activity, due to reduced co-factor binding. All enzymes work at an optimum temperature, in humans this is typically around 98°F (37° C), our core body temperature. The ‘T’ allele makes MTHFR more heat sensitive, meaning that it is less active at our core body temperature. Additionally, MTHFR requires vitamin B2 in order to function correctly, the ‘T’ allele means that MTHFR binds less strongly with vitamin B2 thus showing a reduced function 6.

Reduction in MTHFR activity is linked to reduced levels of MTHF which is required for the conversion of homocysteine to methionine. Homocysteine accumulation is associated with a variety of disorders including cancers, heart disease, stroke, raised blood pressure and potential issues with birth defects.35

For heart disease the largest and most recent study suggests that this effect may be limited to particular population groups or associated with other factors including the rs1801131 (MTHFR A1289C) ‘C’ allele 7,8.

The ‘T’ allele is also assocaited with other ailments including increased migraine frequency and severity, as well as potential digestive issues including IBS and more serious inflammatory bowel disease 9,10.

Direct Nutrients:*

IngredientActive IngredientEffect
Vitamin B2 Riboflavin phosphate

Vitamin B2 is a cofactor for MTHFR which is required to convert MeTHF into MTHF. Vitamin B2 binds with MTHFR and allows it to function optimally, when present in low levels MTHFR activity is reduced. Improving the availability of vitamin B2 may improve the activity of MTHFR, increasing the conversion of MeTHF into MTHF. MTHF is used by methionine synthase to convert homocysteine into methionine, so supplementation with vitamin B2 may lead to a reduction in homocysteine levels. Vitamin B2 is also important in those with excessive folate levels, often associated with cancer and several other diseases, as it increases MTHFR activity, preventing a folate buildup 1113. Supplementation may prove beneficial to those carrying the risk ‘T’ allele of C667T.

Folate Methyltetrahydrofolate

Adequate folate intake is associated with numerous health benefits, hence many western foods, particularly cereals, are fortified with folic acid. However, an excess of folic acid, is associated with an increased risk of developing certain cancers. Therefore, rather than supplementing with folic acid which can accumulate, due to a lack of processing through MTHFR, leading to adverse health effects, MeTHF may be preferred. MeTHF is the substrate which MTHFR converts into MTHF, allowing the one carbon pathway, methionine cycle together forming part of the methylation cycle 1416. Therefore, supplementation may provide benefit to those carrying the risk ‘T’ allele of C667T.

Indirect Nutrients:*

IngredientActive IngredientEffect
Vitamin B6 Pyridoxal phosphate

Vitamin B6 is a cofactor for the enzyme serine hydroxymethyltransferase (SHMT) which converts THF to MeTHF which is in turn converted into MTHF by the enzyme MTHFR. Vitamin B6 binds with SHMT and allows it to function optimally, when present in low levels SHMT activity is reduced.Whilst MeTHF is not typically limited in those with reduced MTHFR activity, this processing can help prevent the buildup of potentially harmful excess levels of folate.
Moreover, two enzymes are required to convert the harmful homocysteine into the amino acid cysteine in the homocysteine transsulfuration pathway: cystathionine β synthase and cystathionine γ ligase. Both of these enzymes also use vitamin B6 as a cofactor, in the absence of vitamin B6 the activity of both enzymes is reduced. Therefore, supplementation with vitamin B6 may ensure that adequate levels of MeTHF are available for MTHFR to process, reduce folate buildup and aid in the conversion of homocysteine into cysteine 1720. Therefore, those carrying the risk ‘T’ allele of C667T may benefit from supplementation.

Vitamin B12 Methylcobalamin

Vitamin B12 is a co-factor for methionine synthase (MS), which converts the harmful homocysteine into the less harmful methionine, also converting MTHF into THF at the same time. Vitamin B12 binds with MS and allows it to function optimally, when present in low levels MS activity is reduced. This activity accounts for approximately half of the processing of homocysteine into methionine. Supplementation with B12 will aid the activity of MS which may help reduce homocysteine levels 2122. Supplementation may therefore prove beneficial to those with the risk ‘T’ allele of C667T.

Betaine

There is another reaction which converts the harmful homocysteine to the less harmful methionine. This reaction is catalyzed by the enzyme betaine homocysteine methyltransferase which uses betaine as a source methyl groups for the formation of methionine from homocysteine. Therefore, supplementing with betaine may reduce the levels of homocysteine, bypassing defective MTHFR activity 23,24. Supplementation may prove therefore prove beneficial in reducing homocysteine levels in those carrying the risk ‘T’ allele of C667T.

Magnesium

Magnesium is one of the most important mineral co-factors around with several hundred enzymes requiring its presence in order to function, as well as other important roles including making ATP (the energy currency of the cell) biologically active.
Magnesium does not appear to be a co-factor for any of the enzymes involved in the one carbon pathway; however, it is a co-factor in for the enzyme acetaldehyde dehydrogenase (ALDH). ALDH is responsible for breaking down acetaldehyde (AH) into acetic acid. Whilst required by the body AH is toxic when present at high levels, indeed AH is the breakdown product of ethanol responsible for many of the symptoms associated with hangovers 25,26.
One of the mechanisms by which AH induces its toxicity is by inhibiting the enzyme methionine synthase which converts the harmful homocysteine into the less harmful methionine. While the symptoms of excessive alcohol intake are short term, AH can accumulate through other means for example when ALDH function is reduced. This is where magnesium comes in, acting as a major cofactor to improve ALDH function. When absent, or present at reduced levels AH can accumulate, inhibiting methionine synthase, which when in conjunction with MTHFR SNPs can rapidly lead to homocysteine accumulation 27,28.

Nutritional Contraindications:*

IngredientActive IngredientEffect
Folic Acid

Adequate folate intake is associated with numerous health benefits, hence many western foods, particularly cereals, are fortified with folic acid. However, an excess of folic acid, is associated with an increased risk of developing certain cancers.
Folic acid is typically rapidly processed through the one carbon pathway; however, reduced MTHFR activity as associated with some MTHFR SNPs can act as a bottleneck promoting the accumulation of MeTHF, and other folate precursors, increasing disease risk as discussed above 2932.

Selenium

Selenium has been associated with a reduction in breast cancer rates, which is thought to be linked to its capacity to reduce DNA methylation. This is a complex topic as DNA methylation can work both ways, with a reductions and increases linked to cancer, depending on the region of DNA which is methylated.
As MTHFR SNPs are already associated with reduced DNA methylation, the further reduction induced by selenium supplementation may be detrimental. A beneficial effect on breast cancer was observed in women with the ‘C’ allele of MTHFR C667T (rs1801133) when they supplemented with selenium. However, in those carrying the risk ‘T’ allele an increase in breast cancer incidence was observed 3336.

C117T

Science Score
Gastrointestinal Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs2066470 c t 10ProPro

Risk Description

Although this SNP is listed on several genetic reports there is no risk currently associated with either allele.

A1298C

Science Score
Brain Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs1801131 a c 30AlaVal

Risk Description

Homozygotes for the risk allele ‘C’ (CC) have approximately 60% reduction in MTHFR activity, there is currently no mechanism to explain how this reduction occurs, or any link to homocysteine levels 37.

Reduction in MTHFR activity is linked to reduced levels of MTHF which is required for the conversion of homocysteine to methionine. Homocysteine accumulation is associated with a variety of disorders including cancers, heart disease, stroke, raised blood pressure and potential issues with birth defects.

However, several large studies have demonstrated a limited effect, suggesting that an effect might only be observed when also present with the rs1801133 (MTHFR C667T) ‘T’ allele 7,8.

Direct Nutrients:*

IngredientActive IngredientEffect
Vitamin B2 Riboflavin phosphate

Vitamin B2 is the cofactor for MTHFR which is required to convert MeTHF into MTHF. Vitamin B2 binds with MTHFR and allows it to function optimally, and when present in low levels MTHFR activity is reduced. Improving the availability of vitamin B2 may improve the activity of MTHFR, increasing the conversion of MeTHF into MTHF and therefore allow proper conversion of homocysteine into methionine 1113. Supplementation may prove beneficial to those carrying the risk ‘C’ allele of A1298C.

Folate Methyltetrahydrofolate

Correct folate intake is associated with several health benefits, especially for infants or during pregnancy. Threrfore, many western foods, particularly cereals, are fortified with folic acid. However, an excess of folic acid, is associated with an increased risk of developing certain cancers. To avoid this effect, rather than supplementing with folic acid which can accumulate, due to a lack of processing through MTHFR, leading to adverse health effects, MeTHF may be used instead. MeTHF is the substrate which MTHFR converts into MTHF, allowing the one carbon pathway, methionine cycle together forming part of the methylation cycle 1416. Therefore, supplementation may provide benefit to those carrying the risk ‘C’ allele of A1298C.

Indirect Nutrients:*

IngredientActive IngredientEffect
Vitamin B6 Pyridoxal phosphate

Vitamin B6 is a cofactor for the enzyme serine hydroxymethyltransferase (SHMT) which converts THF to MeTHF which is in turn converted into MTHF by the enzyme MTHFR. Vitamin B6 binds with SHMT and allows it to function optimally, when present in low levels SHMT activity is reduced. While MeTHF is not typically limited in those with reduced MTHFR activity, this processing can help prevent the buildup of potentially harmful excess levels of folate.
Additionally, two enzymes are required to convert the harmful homocysteine into the amino acid cysteine in the homocysteine transsulfuration pathway: cystathionine β synthase and cystathionine γ ligase. Both of these enzymes also use vitamin B6 as a cofactor, in the absence of vitamin B6 the activity of both enzymes is reduced. Therefore, supplementation with vitamin B6 may ensure that adequate levels of MeTHF are available for MTHFR to process, reduce folate buildup and aid in the conversion of homocysteine into cysteine 1720. Those carrying the risk ‘C’ allele of A1298C may benefit from supplementation.

Vitamin B12 Methylcobalamin

Vitamin B12 is a co-factor for methionine synthase (MS), which converts homocysteine into methionine, also converting MTHF into THF at the same time. Vitamin B12 binds with MS and allows it to function optimally, when present in low levels MS activity is reduced. Supplementation with B12 will aid the activity of MS which may help reduce homocysteine levels 2122. Supplementation may therefore prove beneficial to those with the risk ‘C’ allele of A1298C.

Betaine

The enzyme betaine homocysteine methyltransferase (BHMT) is able to convert homocysteine into methionine using betaine as a methyl donor. Therefore, supplementing with betaine may reduce the levels of homocysteine, bypassing defective MTHFR activity 23,24. Supplementation may prove therefore prove beneficial in reducing homocysteine levels in those carrying the risk ‘C’ allele of A1298C.

Magnesium

Magnesium is a vital mineral co-factor for many enzymes and lays a key role in many other cell functions. Magnesium does not appear to be a co-factor for any of the enzymes involved in the one carbon pathway; however, it is a co-factor in for the enzyme acetaldehyde dehydrogenase (ALDH). ALDH is responsible for breaking down acetaldehyde (AH) into acetic acid. Whilst required by the body AH is toxic when present at high levels, indeed AH is the breakdown product of ethanol responsible for many of the symptoms associated with hangovers 25,26.
One of the mechanisms by which AH induces its toxicity is by inhibiting the enzyme methionine synthase which converts the harmful homocysteine into the less harmful methionine. While the symptoms of excessive alcohol intake are short term, AH can accumulate through other means for example when ALDH function is reduced. This is where magnesium comes in, acting as a major cofactor to improve ALDH function. When absent, or present at reduced levels AH can accumulate, inhibiting methionine synthase, which when in conjunction with MTHFR SNPs can rapidly lead to homocysteine accumulation 27,28.

Nutritional Contraindications:*

IngredientActive IngredientEffect
Folic Acid

Proper folate intake is associated with numerous health benefits especially for young children and pregnant mothers. Therefore, many western foods, particularly cereals, are fortified with folic acid. However, an excess of folic acid, is associated with an increased risk of developing certain cancers.
Folic acid is typically rapidly processed through the one carbon pathway; however, reduced MTHFR activity as associated with some MTHFR SNPs can act as a bottleneck promoting the accumulation of MeTHF, and other folate precursors, increasing disease risk as discussed above 2932.

Selenium

Selenium is associated with a reduction in breast cancer risk, which is thought to be linked to its capacity to alter DNA methylation. Exactly how selenium alters DNA methylation remains unknown.
As MTHFR SNPs are already associated with reduced DNA methylation, the further reduction induced by selenium supplementation may be detrimental. A beneficial effect on breast cancer was observed in women with the ‘C’ allele of MTHFR C667T (rs1801133) when they supplemented with selenium. However, in those carrying the risk ‘T’ allele an increase in breast cancer incidence was observed 3336. It is not clear what effect selenium may have on the risk ‘C’ allele of A1298C.

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

  1. https://www.ncbi.nlm.nih.gov/pubmed/10720211
  2. https://www.ncbi.nlm.nih.gov/pubmed/23116396
  3. https://www.ncbi.nlm.nih.gov/pubmed/7563456
  4. https://www.ncbi.nlm.nih.gov/pubmed/21803414
  5. https://www.ncbi.nlm.nih.gov/pubmed/10090889
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC64948/
  7. https://www.ncbi.nlm.nih.gov/pubmed/27179899
  8. https://www.ncbi.nlm.nih.gov/pubmed/24945727
  9. https://www.ncbi.nlm.nih.gov/pubmed/11121176
  10. https://www.ncbi.nlm.nih.gov/pubmed/10446107
  11. https://www.ncbi.nlm.nih.gov/books/NBK6145/
  12. https://www.ncbi.nlm.nih.gov/pubmed/3676170/
  13. https://www.ncbi.nlm.nih.gov/pubmed/15941973
  14. https://www.ncbi.nlm.nih.gov/pubmed/16638790/
  15. https://www.ncbi.nlm.nih.gov/pubmed/16600944/
  16. https://www.ncbi.nlm.nih.gov/pubmed/18326613/
  17. http://pubs.acs.org/doi/abs/10.1021/bi00759a011
  18. https://www.ncbi.nlm.nih.gov/pubmed/9884399
  19. https://www.ncbi.nlm.nih.gov/pubmed/15539209
  20. https://www.ncbi.nlm.nih.gov/pubmed/9884399
  21. https://www.ncbi.nlm.nih.gov/pubmed/2407589
  22. https://www.ncbi.nlm.nih.gov/pubmed/9884399
  23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515933/
  24. https://www.ncbi.nlm.nih.gov/pubmed/14652361
  25. https://www.ncbi.nlm.nih.gov/pubmed/12206389
  26. http://enzyme.expasy.org/EC/1.2.1.10
  27. https://www.ncbi.nlm.nih.gov/pubmed/4842541
  28. https://www.ncbi.nlm.nih.gov/pubmed/9590515
  29. https://www.ncbi.nlm.nih.gov/pubmed/7469426
  30. https://www.ncbi.nlm.nih.gov/pubmed/16638790/
  31. https://www.ncbi.nlm.nih.gov/pubmed/16600944/
  32. https://www.ncbi.nlm.nih.gov/pubmed/18326613/
  33. https://www.ncbi.nlm.nih.gov/pubmed/9789068
  34. https://www.ncbi.nlm.nih.gov/pubmed/12697962
  35. https://www.ncbi.nlm.nih.gov/pubmed/12154403
  36. https://www.ncbi.nlm.nih.gov/pubmed/25869796
  37. https://www.ncbi.nlm.nih.gov/pubmed/9719624

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