MTHFR gene, methylation and how they affect glutathione production

Methylation is one of body’s most important processes, happening billions of times every second.  However, it is a process mostly unknown to the general population.  Increases in genetic and epigenetic research has led to many people discovering they have mutations MTHFR which can reduce their production of glutathione and increase susceptibility to various diseases.

Genetics and epigenetics

Our genes are made up of DNA.  Previously it was thought that having a gene or genes for certain diseases meant there was nothing that could be done to prevent it, it was just the hand that had been dealt.  However, nowadays this understanding has changed.

While certain genes can predispose individuals to certain illnesses, an individual’s environment, including lifestyle, diet, supplementation and exercise, leads to the expression or silencing of certain genes.  This is the field of study known as epigenetics, our ability to influence the expression of genes.

As the relatively famous (in the fields of genetics and epigenetics) quote goes, ‘genetics loads the gun and environment pulls the trigger.’

Methylation and Epigenetics

Intertwined with the concept of epigenetics is methylation.  Methylation is the process whereby substrates such as DNA, RNA, hormones and neurotransmitters are activated within the body, so that they can complete the tasks they were designed for, including detoxification, neurotransmitter production, energy production, hormonal and metabolic regulation.  Impaired methylation leads to an impairment of these processes, leading to compromised health.

The cycles

There are several pathways involved in methylation including both the folate and methionine cycles.  One of the key nutrients involved in supporting the folate and methionine cycles is (you guessed it) folate.  But not just any form of folate will do.  Folic and folinic acids from supplements as well as dihydrofolate from foods need to be converted to the methylated (active) form of folate, 5-MTHF, to be used within the methionine cycle (Figure 1) (1).

Figure 1 – Folate conversion (1)

As can be seen from Figure 1 conversion of folate to the activated forms requires the enzyme MethyleneTetraHydroFolate Reductase, abbreviated to MTHFR.

The folate cycle intertwines with the methionine cycle (figure 2) leading to methylation of substrates as well as cysteine and taurine production.  The methionine cycle requires the nutrients methionine, serine, ATP, betaine, B6 and B12.  

Methylation and glutathione production

As seen from figure 2, a by-product of the methionine and folate cycles is cysteine.  Methionine is converted to SAM, SAH, homocysteine and then cysteine.  Cysteine, alongside glutamine and glycine are then used to produce the intracellular antioxidant glutathione.  This is known as the transsulfuration pathway.  

Besides requiring adequate amounts of activated folate and activated B12, the body requires vitamin B6 and serine to convert homocysteine into cysteine which can then be used to manufacture glutathione.

It may therefore come as no surprise that low amounts of these nutrients, alongside MTHFR genetic mutations can reduce the amount of glutathione produced and increase susceptibility to illness from environmental toxin exposure (2)

Figure 2 – Methionine and Folate cycles (2)

MTHFR gene

MTHFR genetic mutations can lead to homocysteine build up (2).  Ultimately, this can lead to both reduced production of glutathione and increased oxidative stress and inflammation via homocysteine build up (3, 4, 5).

Regarding genetic testing, the MTHFR C677T and MTHFR A1298C SNPs are currently tested for and studied for their impacts on methylation.  These genetic mutations lead to a decrease in the activity of the MTHFR enzyme, reducing the conversion of folate to its active form by 20-70% and therefore reducing glutathione levels (6, 7, 8).

 What can be done about glutathione?

Fear not, an MTHFR mutation doesn’t have to translate to low glutathione!

Currently, if somebody presents with an MTHFR mutation, they are likely to come across information that they only need to take supplemental 5MTHF, the activated form of folate, to improve their methylation.  However, folate activation represents just one part of these cycles.  It is just as important to maintain adequate B6, B12 and betaine levels to ensure this pathway flows smoothly at all levels, including down the transsulfuration pathway to manufacture glutathione. 

The transsulfuration pathway, however, represents only one way that glutathione can be produced from increasing cysteine levels.  Beyond being produced within the body, cysteine can of course be derived from the diet and supplementation and transported into the cell via the ASC system and X_c- system (9).

It is important to note that glutathione is produced from cysteine, glycine and glutamine, thus maintaining adequate levels of both glycine and glutamine are also necessary to upregulate glutathione production.  

Conclusion

There is so much more to methylation than MTHFR and folate.  An impairment in the methionine and folate cycles can lead to both a reduction in the production of glutathione and an increase in the compound homocysteine, a compound associated with oxidative stress and decreased glutathione levels.  Fear not, there are ways to improve functioning of these cycles as well as alternate ways to improve glutathione production, via optimising cysteine, glutamine and glycine levels.

References: 

1. Fava, M. and Mischoulon, D., 2009. Folate in depression: efficacy, safety, differences in formulations, and clinical issues. Journal of Clinical Psychiatry, 70(5), pp.12-17.
2. Miller, A.L., 2003. The methionine-homocysteine cycle and its effects on cognitive diseases.(Homocysteine & Cognitive). Alternative Medicine Review, 8(1), pp.7-20.
3. Miller, A.L., 2003. The methionine-homocysteine cycle and its effects on cognitive diseases.(Homocysteine & Cognitive). Alternative Medicine Review, 8(1), pp.7-20.
4. Kennedy, D., 2016. B vitamins and the brain: mechanisms, dose and efficacy—a review. Nutrients, 8(2), p.68.
5. Gopinath, B., Flood, V.M., Rochtchina, E., Wang, J.J. and Mitchell, P., 2013. Homocysteine, folate, vitamin B-12, and 10-y incidence of age-related macular degeneration. The American journal of clinical nutrition, 98(1), pp.129-135.
6. Nazki, F.H., Sameer, A.S. and Ganaie, B.A., 2014. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene, 533(1), pp.11-20.
7. Friso, S., Choi, S.W., Girelli, D., Mason, J.B., Dolnikowski, G.G., Bagley, P.J., Olivieri, O., Jacques, P.F., Rosenberg, I.H., Corrocher, R. and Selhub, J., 2002. A common mutation in the 5, 10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proceedings of the National Academy of Sciences, 99(8), pp.5606-5611.
8. Fisher, M.C. and Cronstein, B.N., 2009. Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. The Journal of rheumatology, 36(3), pp.539-545.
9. Lu, S.C., 2013. Glutathione synthesis. Biochimica et Biophysica Acta (BBA)-General Subjects, 1830(5), pp.3143-3153.