MTHFR

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 ^11–13. Supplementation may prove beneficial to those carrying the risk ‘T’ allele of C667T.

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 ^14–16. Therefore, supplementation may provide benefit to those carrying the risk ‘T’ allele of C667T.

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 ^17–20. Therefore, those carrying the risk ‘T’ allele of C667T may benefit from supplementation.

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 ^21–22. Supplementation may therefore prove beneficial to those with the risk ‘T’ allele of C667T.

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 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.

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 ^29–32.

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 ^33–36.

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 ^11–13. Supplementation may prove beneficial to those carrying the risk ‘C’ allele of A1298C.

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 ^14–16. Therefore, supplementation may provide benefit to those carrying the risk ‘C’ allele of A1298C.

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 ^17–20. Those carrying the risk ‘C’ allele of A1298C may benefit from supplementation.

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 ^21–22. Supplementation may therefore prove beneficial to those with the risk ‘C’ allele of A1298C.

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 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.

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 ^29–32.

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 ^33–36. It is not clear what effect selenium may have on the risk ‘C’ allele of A1298C.