Methylation is one of the most essential and ubiquitous metabolic functions of the body, and as such, is fundamental to how we feel physically, mentally and emotionally on a day-to-day basis.  

Put simply, methylation involves the transfer of a methyl group (one carbon atom and three hydrogen atoms) onto another molecule, and it occurs in every tissue and cell of the body.

Catalysed by a variety of enzymes and nutrients, the methylation cycle contributes to a wide range of critical bodily functions that enable it to adapt, repair, detoxify and respond to both internal and external stressors. Key functions affected by the cycle include genetic expression and DNA repair, immune response, detoxification, neurotransmitter synthesis, mitochondrial function and energy production.^1,2

Current research indicates that between 60-70 percent of individuals will have a mutation of the methylene tetrahydrofolate reductase (MTHFR) gene, a genetic variation that results in reduced enzyme activity and subsequently, a reduction in the availability of methyl groups.^3,4 Poor diet and lifestyle choices, chronic stress and the inevitable aging process can also negatively impact a person’s capacity to methylate. It’s when methylation becomes compromised that important biochemical functions can no longer be carried out appropriately, resulting in irregularities in cellular metabolism and ultimately - inefficient energy production.⁵

Figure 1. The interrelationship between chronic fatigue and methylation dysfunction.⁶

Fatigue is one of the top complaints I hear from patients in clinic, and is an indication that the body is depleted and not functioning optimally. Biochemical processes reliant on healthy methylation which may contribute to fatigue include:

• Creatine supplies energy to all cells in the body by recycling adenosine diphosphate (ADP) to adensoine triphosphate (ATP), the energy currency of the cell. However, creatine synthesis requires methyl groups, and variations in the MTHFR gene can result in a creatine deficiency, causing reduced energy levels and fatigue.⁷
• Carnitine plays a crucial role in lipid metabolism by transporting long chain fatty acids into the mitochondria where they undergo beta-oxidation to produce energy in the form of ATP. Reduced methylation activity reduces methionine synthesis, a necessary substrate for the manufacture of carnitine. Therefore, without effective methylation energy is not adequately supplied to the cells, resulting in fatigue.⁸
• Coenzyme Q10 (CoQ10) is the main component of the electron transport chain which generates ATP in mitochondria. The synthesis of CoQ10 is dependent on s-adenosylmethionine (SAMe) as the methyl donor. Thus, compromised methylation results in reduced CoQ10 synthesis and lower overall energy production.⁹
• Glutathione is known as the ‘master antioxidant’ of the body and under-functioning of the methylation cycle can result in low levels. When glutathione levels get too low in muscle cells, levels of oxidizing free radicals increases, resulting in reduced cellular ATP production and fatigue. Glutathione is also required for the proper functioning of vitamin B12, which plays a significant role in energy production, making red blood cells for oxygen delivery, and reducing oxidative stress.¹⁰

Nutrient deficiency is one of the main causes of impaired methylation, and while many people think primarily of folate and vitamin B12 as perhaps the most important nutrients for methylation, an inadequate intake of other nutrients will also have a significant impact on our ability to methylate.¹¹

In line with this, research is now starting to highlight the importance of activated B vitamins as cofactors to support critical enzymes integral to the methylation pathway.

• Pyridoxal 5’-phosphate (P5P) as the active coenzyme form of vitamin B6, can be directly utilised by the body without conversion. Almost every biochemical reaction involving amino acids requires P5P, as it is a vital cofactor for transaminase enzymes.^12,13
• 5-Methyltetrahydrofolate (5-MTHF) as the metabolically active form of folic acid, acts as a methyl donor to create methylcobalamin, used for remethylation of homocysteine to methionine. During absorption and transport, folic acid undergoes a series of reactions to form 5-MTHF. However, this process is inefficient in individuals with MTHFR gene mutations due to reduced enzyme activity. As such, supplementing with the already activated form of folate (5-MTHF) is a far more effective approach.¹⁴
• Methylcobalamin, the active form of vitamin B12, is the most common form of vitamin B12 found in the serum. It is preferential to supplement with this form of cobalamin as it is the essential cofactor for methionine synthase, which accepts methyl groups from 5-MTHF and re-methylates homocysteine to form methionine.¹⁵
• Vitamin B2 in its active form of riboflavin sodium phosphate, plays an essential role in the homocysteine metabolic pathways of re-methylation and trans-sulfuration. In addition, both PLP and 5-MTHF require the active form of riboflavin for their synthesis.¹⁶
• While not an activated B vitamin, choline may be just as important as 5-MTHF and vitamin B12 for promoting a fully functioning methylation cycle. Trans-methylation metabolic pathways closely interconnect choline, methionine, 5-MTHF and vitamins B6 and B12. The pathways intersect at the formation of methionine from homocysteine. As such, a deficiency of choline can put an increased additional burden on methylation levels in those exhibiting insufficient methylation capacity.¹⁷

Given that methylation affects so many processes in the body and underpins so many chronic health conditions, supporting methylation should always be a consideration in any patient treatment protocol, especially for those patients presenting with fatigue.

We don’t have all of the answers yet, in terms of the how reduced methylation capacity impacts our overall health and wellbeing, but the good news is that we now have ways to bypass several genetic variations that we do know about. Genetics aren’t everything, but ultilising specific targeted nutrients is one way that we can assist in restoring normal functioning to the body in those patients who are depleted and suffering.

References

1. Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate's Role. Adv Nutrs. 2012;3(1):21-38.
2. Anderson OS, Sant KE, Dolinoy DC. Nutrition and epigenetics: An interplay of dietary methyl donors, one-carbon metabolism, and DNA methylation. J Nutr Biochem. 2012;23(8):853-859.
3. Burda P, Schafer A, Suormala T, et al. Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients. Hum Mutat. 2015;36(6):611-621.
4. Wilcken B, Bamforth F, Li Z, et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003;40(8):619-625.
5. Moore LD, Le T, Fan G. DNA Methylation and Its Basic Function. Neuropsychopharmacology. 2013;38(1):23-38.
6. Ledowsky C. Is your chronic fatigue due to the MTHFR gene? 2017; https://www.mthfrsupport.com.au/chronic-fatigue-due-mthfr-gene/. Accessed 02-04-2018.
7. Guimarães-Ferreira L. Role of the phosphocreatine system on energetic homeostasis in skeletal and cardiac muscles. Einstein. 2014;12(1):126-131.
8. da Silva RP, Kelly KB, Al Rajabi A, Jacobs RL. Novel insights on interactions between folate and lipid metabolism. Biofactors (Oxford, England). 2014;40(3):277-283.
9. Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. BBA - Biomembranes. 2004;1660(1):171-199.
10. Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014;12(2):168-185.
11. Anderson OS, Sant KE, Dolinoy DC. Nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. J Nutri Biochem. 2012;23(8):853-859.
12. Lumeng L, Lui A, Li TK. Plasma content of B6 vitamers and its relationship to hepatic vitamin B6 metabolism. J Clin Invest. 1980;66(4):688-695.
13. Dalto DB, Matte J-J. Pyridoxine (Vitamin B(6)) and the Glutathione Peroxidase System; a Link between One-Carbon Metabolism and Antioxidation. Nutrients. 2017;9(3):189.
14. Miller AL, Kelly GS. Methionine and homocysteine metabolism and the nutritional prevention of certain birth defects and complications of pregnancy. Alt Med Rev. 1996;1(4):220-235.
15. Duncan TM, Reed MC, Nijhout HF. The relationship between intracellular and plasma levels of folate and metabolites in the methionine cycle: A model. Mol Nutr Food Res. 2013;57(4):628-636.
16. Marashly ET, Bohlega SA. Riboflavin Has Neuroprotective Potential: Focus on Parkinson’s Disease and Migraine. Front Neurol. 2017;8:333.
17. Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr. 2002;132(8 Suppl):2333s-2335s.