Understanding the Methylation Cycle and Its Effect on Health

Naturopathic Doctor Doni Wilson explains how our genetic makeup defines which enzymes need extra support in your body and the role the methylation cycle plays.

Part 3 of Dr. Doni’s Series on How Genetic Mutations Affect Your Health

genetic health conditions, genetic mutation, chronic health issues, methylation, methylation cycle, genetic testing, genetic treatments, MTHFR, MTHFR mutations, SNP, single-nucleotide polymorphismIn the first two parts of this blog series, we explored how genetic mutations (or SNPs) can affect our health and how we go about finding out which SNPs you have as the first step on the road to optimal health. If you missed them and wish to catch up, here are links to the first two articles plus what’s coming up next time:

Understanding your genetic mutations (SNPs) will help you identify which processes and enzymes may need support in your body. Once you have this information you’ll be able to design exactly the right support for your body including making the right diet choices (avoiding food sensitivities), taking the right nutrients and optimizing the way in which you respond to stress, all based on your individual needs.

Today I’m going to discuss the enzymatic pathways in the methylation cycle that influence not only the way you feel from day to day but also your risk of disease in the long run. Then, next week, I will share my 8 steps to a healthy methylation cycle. (I find it quite something that I’m helping Ella study for her first chemistry test while writing this article about the biochemistry in our bodies.) First, before diving into the enzymes, let’s talk about why the methylation cycle is important and how it affects your health.

Why is The Methylation Cycle Important?

The methylation cycle is important because it takes the nutrients from our food (and vitamins) to make the energy our bodies need to work properly. It also makes healthy cells and balances our mood as well as removing toxins and fighting infections. It is quite amazing when you think about it that the processes involved can have such a significant influence throughout your body. When methylation is working, you’ll feel full of energy, in a good mood; you will feel generally well. When it is not working, you will feel tired, depressed, irritable, run-down, susceptible to infections, foggy-brained, and just plain “toxic.”

Understanding the methylation cycle starts with thinking of dominos lined up in a circular pattern. Just as when the dominos start to fall—each domino toppling the next—when enzymes start processing nutrients, one enzyme affects the next. And just as with dominos, if one is out of line and doesn’t topple onto the next one (or it stops working), it causes a backup that inhibits the enzymes that follow and this, in turn, affects how we feel and how well we function. More specifically:

  1. Research shows that decreased function of the enzymes in the methylation cycle can affect your health and increase your risk of heart disease, cancer, chronic fatigue, mood disorders, diabetes, and aging in general. If you want to read more on this subject you can check out the research studies listed at the end of this article.
  1. These enzymes are important for mitochondrial function and energy production. Low mitochondrial function and low methylation can lead to low energy, low thyroid function, decreased memory, and more. Read more about mitochondria in this article.
  1. These enzymes also affect your:
    – neurotransmitter levels, which can lead to anxiety and depression,
    – immune function, including the likelihood that you’ll experience allergies this spring,
    – liver detoxification, which has to do with how your body gets rid of toxins, and
    – fertility, including risk of miscarriage
  1. The end result of these enzyme pathways (the domino line) is the production of glutathione, a major antioxidant and protector of your cells.
  1. Ultimately these enzyme pathways affect the ability of your body to make new healthy cells.

The Key Enzymes (the science bit):

Enzymes are given nicknames based on the first letter of each of the chemical words in their name. So they are often called by 3 or 4 capital letters, the last of which describes that enzyme’s function. For example, R stands for reductase, and T is for transferase (it transfers a molecule from one substance to another). I don’t want you to have to worry too much about those details. What is more important is to understand how the enzymes relate to one another and where they lead in the end. For now, here are the enzymes that are involved in the methylation cycle and what they do:

  • MTHFR – stands for Methylenetetrahydrofolate reductase. It converts folic acid to methylfolate (5MTHF)
  • MTR – Methionine Synthase uses methylfolate (folate) and methylcobalamin (B12) to turn homocysteine into methionine
  • MTRR – Methionine Synthase Reductase creates SAM and electrons that make energy in the mitochondria
  • BHMT – The backup system (so to speak) in the liver and kidneys that can also make methionine from choline and TMG
  • CBS – Removes homocysteine from the MTR/MTRR cycle and converts it into cysteine and glutathione

How Do These Enzymes Affect Each Other?

This is where it gets very science-y and complicated. I’ll try and explain it as simply as possible.

The methylation pathway starts with MTHFR, which you can read more about here. Research indicates that at least 45% of people have at least one MTHFR mutation and, as a consequence, have a 40% decreased ability to process folic acid (the process doesn’t actually stop; it merely decreases). If you have an MTHFR mutation, your body is less able to use folic acid in the methylation cycle, which can increase your risk for the conditions we discussed above, including:

  • heart disease
  • anxiety
  • miscarriages
  • fatigue

The best treatment is for you to avoid folic acid and instead consider taking methylfolate, starting with low dosages so that your methylation cycle gets the nutrients it needs to keep you healthy. It’s important you do this under the care of a practitioner to ensure you are taking the right dosage and that it is having the desired effect.

Once you have methylfolate in your system, it connects with the next ‘dominos’ in the chain–MTR, MTRR, BHMT (a shortcut through the middle of the methylation cycle that allows your body to use choline (such as from eggs, shrimp, poultry, salmon, and leafy greens) instead of folate and B12 to add methyl to the cycle), and finally CBS.

Knowing which genetic mutations you have is useful because if, for example, you have SNPs in MTR or MTRR then your body may do better if you take a supplement* containing adenosyl or hydroxocobalamin that allow you to skip past MTR and MTRR to produce the necessary methyl.

MTR uses two enzymes (methylfolate and methylcobalamin—a form of vitamin B12) to turn a substance called homocysteine into another, called methionine. Then, in the next step, MTRR uses methionine to make yet another crucial substance (SAM or S-Adenosyl Methionine).

The end result of this particular domino line creates a much needed methyl group on a SAM which is then passed on to other pathways that protect your DNA and cells, and make your neurotransmitters and other important substances. At the same time, an electron is produced that allows your mitochondria to make energy. This turns SAM back into homocysteine so it is ready to go around the cycle again (unlike dominos, in our bodies, the process is continuous).

The final enzyme in this process is called CBS; this acts as the methylation cycles built-in ‘drain’ by removing homocysteine and using it to process ammonia and make glutathione. Glutathione is our most important anti-oxidant, so SNPs on CBS can make for increased oxidative stress and higher ammonia levels, leading to fatigue and achiness.

Where Do We Run Into Trouble?

The methylation cycle is super sensitive to stress! When you are emotionally or physically stressed (and your cortisol levels increase), the enzymes slow down and the amount of methyl produced decreases. At the same time, your body needs more methyl to help process the adrenaline produced by stress. This means that right when you are most stressed, you are more likely to feel worse! It is when you are stressed that you have an increased need for the nutrients that help your enzymes work well.

Things that bring stress to your methylation cycle include:

  • Oxidative stress, read more in this article
  • Alcohol (yes, as in wine, beer and liquor)
  • Yeast die off, from having and treating yeast (also known as candida or thrush) whether with herbs or medications
  • Elevated nitric oxide, which is common with chronic fatigue, inflammation, autoimmunity and Lyme disease; nitrous oxide gas treatment at the dentist will also increase nitric oxide
  • Autoimmune antibodies
  • Food sensitivities and leaky gut, read more in this article
  • Toxins in the environment
  • Heavy metals (like mercury and aluminum)

Where to Go From Here?

As we discussed in the article last week, there are specialized tests that can tell us what genetic mutations (SNPs) you have and help us understand where things are stuck and which nutrients your body needs. Next week I will talk about what you can do to improve your methylation. Of course, it’s easier to make the right diet and nutrient choices if you know which SNPs you have and how they affect the processes in your body.

If you would like to explore this further you may want to check out my Genetic Profiling Solutions Package here. With this package you’ll meet with me in-person or by phone/Skype to review your case and records. Then I’ll be able to help you with genetic testing and panels to help us know how your body is being affected by mutations so that we can then create a clear plan for you including diet recommendations and supplements. If you are not sure about the whole package, then you can start with a Comprehensive Health Breakthrough initial consultation with me and then we can decide what is needed from there to implement the steps I am outlining in this series of articles.

In the coming weeks I will be describing other SNPs in more detail; the conditions associated with them and ways to support them in order to optimize your health. To be sure you get these articles, you can subscribe to my blog feed to the right of this post or to my newsletter below.

–Dr Doni
27th March 2015

Further Reading

Lin PT1, Cheng CH, Wei JC, Huang YC. Low plasma pyridoxal 5′-phosphate concentration and MTHFR 677C–>T genotypes are associated with increased risk of hypertension. Int J Vitam Nutr Res. 2008 Jan;78(1):33-40.

Qi YH1, Yao LP2, Cui GB3, Liang J1, Shao QJ1, Yan LF3, Du P4. Meta-analysis of MTHFR C677T and A1298C gene polymorphisms: association with the risk of hepatocellular carcinoma. Clin Res Hepatol Gastroenterol. 2014 Apr;38(2):172-80.

Sohn KJ1, Jang H, Campan M, Weisenberger DJ, Dickhout J, Wang YC, Cho RC, Yates Z, Lucock M, Chiang EP, Austin RC, Choi SW, Laird PW, Kim YI. The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification. Int J Cancer. 2009 May 1;124(9):1999-2005.

Wang LJ1, Lee SY2, Chen SL3, Chang YH4, Chen PS5, Huang SY6, Tzeng NS6, Chen KC5, Lee IH5, Wang TY5, Yang YK5, Lu RB7.  A potential interaction between COMT and MTHFR genetic variants in Han Chinese patients with bipolar II disorder. Sci Rep. 2015 Mar 6;5:8813.

Schmechel DE1, Edwards CL. Fibromyalgia, mood disorders, and intense creative energy: A1AT polymorphisms are not always silent. Neurotoxicology. 2012 Dec;33(6):1454-72.

Gilbody S1, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007 Jan 1;165(1):1-13. Epub 2006 Oct 30.

Qin X1, Li Y, Yuan H, Xie D, Tang G, Wang B, Wang X, Xu X, Xu X, Hou F. Relationship of MTHFR Gene 677C→T Polymorphism, Homocysteine, and Estimated Glomerular Filtration Rate Levels With the Risk of New-Onset Diabetes. Medicine (Baltimore). 2015 Feb;94(7):e563.


*Please keep in mind that any and all supplements—nutrients, herbs, enzymes, or other—should be used with caution. My recommendation is that you seek the care of a naturopathic doctor (with a doctorate degree from a federally-accredited program) and that you have a primary care physician or practitioner whom you can contact to help you with individual dosing and protocols. If you ever experience negative symptoms after taking a product, stop taking it immediately and contact your doctor right away.


  1. I understand that the RBS’s store 95% of your body’s folate. If one has the dual heterozygous genotype for the MTFR C677T (C/T) and MTHFR A1298C (A/C) and RBC folic acid levels of 1488 ng/ml and serum B12 of >1000pg/ml should that person take a supplemental methylated folate? Are the blood levels elevated due to substrate accumulation from decreased metabolic conversion in other pathways, or can they be increased or normal due to adequate intake nutritionally? (assuming no B12 or folate being taken as a vitamin). With the concern for increased methylation of cancer suppressor genes, should these people add in L-methyl folate or not?

    • Hi Linda, I assume you are referring to RBC folate and serum B12 from a standard lab – in which case I would say that the levels are really not going to help us to know whether you should or shouldn’t take folate. Best is to run a homocysteine level so you get a sense of methylation. Then, when I really want to know a patient’s folate level, I go to a specialty lab that can give us the most accurate information.