The Methylation Cycle And Active Methyl B-12 and Methyl Folate

When I first learned about the methylation cycle in med school, it was more about memorizing the pathway and acronyms to pass the exam. It wasn’t until after I faced my own health crisis that led me down the path of functional medicine that methylation became less of a concept and more of a concrete piece of my healing. I finally saw just how important nutrition – and especially the B vitamins – are for turning the biochemical wheels in every cell of the body.

This allowed me to link my daily health habits, including my diet and daily supplements to how I was feeling as I saw my fatigue diminish and health improve. It really helped me to understand the science of methylation as a doctor diving into its biochemistry, as well as its importance as a patient on my own path to optimal wellness.

That’s what I hope to do here for you today in this article. I’m going to break down methylation so you can see how intricate this seemingly simple process is and why having good B vitamin status, especially vitamin B12 and folate, is so important for maintaining a well-oiled methylation cycle.

Methylation is happening in every cell of your body, even right now, as you read this! And by the time you are done with this article, the methylation cycle will have turned billions of times.

Keep reading to learn more about:

• What, exactly, is methylation?
• What is the methylation cycle? – with a helpful visual!
• What is MTHFR?
• Why to care about homocysteine levels? – with another helpful visual!
• What impacts methylation?
• How to use active folate and vitamin B12 for methylation support?

Let’s get started!

What Is Methylation?

Simply put, methylation is the addition of a methyl group – a carbon atom attached to three hydrogens (CH₃) - to a molecule, such as an enzyme, hormone or DNA. It may seem simple, but methylation is one of the most important chemical reactions in the body, occurring billions of times per second.

Methylation impacts biochemical reactions throughout the body. Methylation is important for:

• Detoxification
• Neurotransmitter production
• Hormone metabolism
• Histamine metabolism
• DNA/genetic expression
• Amino acid metabolism
• Growth and development

Although its appears at first glance to be a simple concept (it’s about the proper transfer of a methyl group) for all of the important processes in the body it impacts, there is much more to the story. Understanding the methylation cycle allows us to see all of the players and important nutrients that go into methylation.

What Is The Methylation Cycle?

Since a picture is worth a thousand words, this visual of the methylation cycle helps us to see the intricacies.

The methylation cycle, as pictured above, is the biochemical process that allows the body to move a methyl group that can go on to attach to various molecules to activate DNA, detoxify estrogen and perform other important cellular functions. 

Here is the big picture: a series of enzymes (in black boxes) help the body recycle homocysteine back into methionine, both of which are proteins. As the gears in this process turn, a methyl group passes from folate (vitamin B9), with the help of vitamin B12.

As methionine, turns back into homocysteine it release an important molecule called SAM-e (s-adenosyl methionine), which is the most important methyl donor in the body. It’s called a methyl donor because it carries the methyl group from this process in order to attach it to another molecule (DNA, enzymes, protein, hormones, etc.) so they can perform their functions.

This may look a little like the Citric Acid Cycle you’ve seen me talk about in previous articles. With the Citric Acid Cycle, the cycle turns and ATP is produced for energy, but with the methylation cycle as the cycle turns, it churns out methyl donors, i.e. SAM-e. And like the Citric Acid Cycle, B vitamins are the stars of the show.

MTHFR And 5-MTHF

Let’s take a closer look at the left hand cycle, or gear, in the diagram above. You’ve likely heard of MTHFR, which stands for MethyleneTetraHydroFolate Reductase, which is an enzyme that converts an inactive form of folate (vitamin B9) into its active form, 5-MTHF.

“Active” folate is different than synthetic “folic acid” found in over the counter supplement products. Folic acid is not found in nature and is actually quite difficult to convert into active folate 5-MTHF for a lot of people.

What you need to understand here is that it’s the active form of folate that the methylation cycle, and ultimately the body, needs.

When you take folic acid (synthetic) or another form of folate, the body must go through this cycle to methylate it in order for use. Folate and vitamin B12 (as methyl-B12) work hand-in hand to pass the methyl group through the cycle. Vitamin B2 (riboflavin) and vitamin B3 (niacin) play a role here as well.

“MTHFR” is an enzyme that makes active folate is also used to refer to the MTHFR gene that codes for this critical enzyme. Many of us have variations in the genetic code for this enzyme called a SNP (“snip”) or Single Nucleotide Polymorphism. This means that there is one small change to the genetic code and in some cases, it is possible that it affects the body’s ability to methylate. Two specific variations in the MTHFR gene (C677T and A1298C) are widespread in the population and associated with a mild to severe deficiency in the MTHFR enzyme. (Source 1)

For example, we carry two copies of each gene in our cells. If one copy of the MTHFR gene has a SNP mutation the efficiency of the enzyme is creates make be mild. If both copies of the gene are mutated, then the efficiency of the MTHFR enzymes in churning out active folate could be cut by as much as 75%.

You can find out if you have a MTHFR mutation by asking your doctor to run for a simple blood test available both through Quest or Labcorp. More and more doctors are testing for this gene that codes for such an important enzyme routinely. Here is why…

MTHFR and poor methylation is linked to:

• Elevated homocysteine, which is associated with heart disease and stroke (Source 2)
• Schizophrenia, major depression and bipolar disorder (Source 3)
• Dementia and Alzheimer’s (Source 4)
• Chronic fatigue and fibromyalgia (Source 5)
• Infertility and miscarriage (Source 6)
• Birth defects including spina bifida (Source 7)
• Cancer (Source 8, 9)
• Autoimmune conditions, including Hashimoto’s thyroiditis (Source 10)

By now you are getting the idea that methylation is very important and when impaired, it has far reaching impacts to the body.

Understanding Homocysteine Metabolism

Let’s talk a little bit more about homocysteine metabolism. If the cycle isn’t turning properly you’ll see a change in homocysteine levels that can be measured in the blood. If homocysteine is high, this might indicate poor methylation and the need for more B vitamins and/or minerals.

Homocysteine is of concern primarily because when elevated, it is associated with cardiovascular disease and normalizing homocysteine levels, with the use of B vitamins, slows disease progression. (Source 2)

Take a look at this visual which highlights the most important B vitamins in this process.

As you can see, if homocysteine accumulates, B vitamins can help move it along. There are 3 ways to support this biochemical balance:

1. Homocysteine turns back into methionine with the help of vitamin B12 and folate (as 5-MTH), as discussed above. The key enzyme here is methionine synthase (MTR). (Source 11)

2. Homocysteine can take a “short cut” to methionine with the help of a molecule called betaine derived from the B vitamin choline. The key enzyme here is betaine homocysteine methyltransferase or BHMT. (Source 12)

3. Homocysteine can be converted to the amino acid cysteine, with the help of vitamin B6 (in its active form pyridoxal 5’-phosphate or PLP). Two enzymes are needed here: cystathionine beta synthase (CBS) and cystathionine gamma lyase. Cystathionine is the intermediate compound. (Source 13). This pathway leads to the conversion of cysteine to the important master antioxidant and detoxifier: glutathione. Further down this pathway, as seen in the first diagram, sulfates turn to sulfites with the help of the sulfite oxidase (SUOX) enzyme in order to excrete excess sulfur from the body as homocysteine breaks down.

What Affects Methylation?

Now that you have a detailed picture of the methylation biochemistry in the body, let’s take a wider view about the role this plays in your life.

When it comes to methylation, we want to be Goldilocks: not too much nor too little methylation.

It’s possible to be a good methylator and have an MTHFR mutation, or it’s possible to have picture perfect genetics, but have poor methylation. Why? There are so many factors that determine how your body methylates. 

MTHFR SNPs are just one factor that affects methylation; here are some others:

• SNPs in the code for other key methylation enzymes: BHMT, MTR, MTRR (needed for vitamin B12 recycling), CBS, SUOX and others. Again, ask your integrative or functional medicine doctor to test for all of these key enzymes.
• Widespread and consistent dietary sources of folate, vitamin B12 and other key methylation nutrients.
• Ability to absorb these key micronutrients.
• Body burden of toxins (since methylation is required for detoxification).
• Alcohol use or abuse that depletes B vitamins.
• Stress that depletes B vitamins.

When you take into account all of these lifestyle factors, and the modern environment in which we live, you can see that many of us might need more B vitamins in order to support healthy and balanced methylation in the body. This is where active B vitamin supplements come in with Vitamin B12 as the king and Folate as the queen of the Bs!

Active B-12 And Active Folate For Methylation Support

One of the quickest and most effective ways to boost your body’s ability to methylate is by supplying the active, methylated, forms of folate (as 5-methylfolate or 5-MTHF) and vitamin B12 (as methylcobalamin/methyl-B12 and adenosylcobalamin). Since vitamin B12 deficiency and folate deficiency are quite common, and our needs might be greater because of genetic SNPs or environmental factors, an easy supplement has far reaching affects.

You might notice more energy, clearer thinking, improved moods and even reduced risks or symptoms from some of the conditions discussed here.

Active B vitamins are often a part of a quality comprehensive multivitamin, and for additional B12 and folate, I recommend a sublingual form. By dissolving this supplement under the tongue, you bypass the digestive system, and any issues with absorption. Sublingual tablets can also be cut if a smaller dose is desired.

Core Med Science’s Active Methyl B12 and 5-MTHF Lozenge provides the active nutrients, in a therapeutic, yet not too high of a dose. In addition, this product is non-GMO, soy-free, dairy-free, third party tested and made in the U.S. 

If you prefer not to use a sublingual lozenge, an equally high-absorption alternative is to use our B-Complex multivitamin, which provides high levels of B12 and folate in their active methylated forms along with all of the important methylation cycle mineral catalysts such as manganese and molybdenum.

The passing of a methyl group between molecules over and over again is a simple, complicated and beautiful process that allows us to do all of the things that make us human. And one that we don’t have to think about at all, until perhaps it isn’t working as efficiently as we would like.

In this article, I really zoomed in to the details of the methylation cycle to highlight the importance of the B vitamins, especially folate and vitamin B12. I want to leave you with the bigger picture that your daily health habits and lifestyle are a powerful regulator of methylation. If you are stressed, eating processed foods and sedentary this will negatively impact methylation. However, exercise, meditation, nutrient-dense foods, good sleep and other healthy behaviors help to bring methylation into balance. A high quality B12 and folate supplement just might be icing on the cake!

References

1. Levin, B. L., & Varga, E. (2016). MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature. Journal of genetic counseling, 25(5), 901–911. Abstract: https://pubmed.ncbi.nlm.nih.gov/27130656/
2. Kalra D. K. (2004). Homocysteine and cardiovascular disease. Current atherosclerosis reports, 6(2), 101–106. Abstract: https://pubmed.ncbi.nlm.nih.gov/15023293/
3. Wan, L., Li, Y., Zhang, Z., Sun, Z., He, Y., & Li, R. (2018). Methylenetetrahydrofolate reductase and psychiatric diseases. Translational psychiatry, 8(1), 242. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218441/
4. Román, G. C., Mancera-Páez, O., & Bernal, C. (2019). Epigenetic Factors in Late-Onset Alzheimer's Disease: MTHFR and CTH Gene Polymorphisms, Metabolic Transsulfuration and Methylation Pathways, and B Vitamins. International journal of molecular sciences, 20(2), 319. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359124/
5. Regland, B., Forsmark, S., Halaouate, L., Matousek, M., Peilot, B., Zachrisson, O., & Gottfries, C. G. (2015). Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. PloS one, 10(4), e0124648. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406448/
6. Zhu, Y., Wu, T., Ye, L., Li, G., Zeng, Y., & Zhang, Y. (2018). Prevalent genotypes of methylenetetrahydrofolate reductase (MTHFR) in recurrent miscarriage and recurrent implantation failure. Journal of assisted reproduction and genetics, 35(8), 1437–1442. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086799/
7. Martinez, C. A., Northrup, H., Lin, J. I., Morrison, A. C., Fletcher, J. M., Tyerman, G. H., & Au, K. S. (2009). Genetic association study of putative functional single nucleotide polymorphisms of genes in folate metabolism and spina bifida. American journal of obstetrics and gynecology, 201(4), 394.e1–394.11. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790326/
8. Gong, J. M., Shen, Y., Shan, W. W., & He, Y. X. (2018). The association between MTHFR polymorphism and cervical cancer. Scientific reports, 8(1), 7244. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940696/
9. Xu, L., Qin, Z., Wang, F., Si, S., Li, L., Lin, P., Han, X., Cai, X., Yang, H., & Gu, Y. (2017). Methylenetetrahydrofolate reductase C677T polymorphism and colorectal cancer susceptibility: a meta-analysis. Bioscience reports, 37(6), BSR20170917. Full text:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719002/
10. Arakawa, Y., Watanabe, M., Inoue, N., Sarumaru, M., Hidaka, Y., & Iwatani, Y. (2012). Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease. Clinical and experimental immunology, 170(2), 194–201. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482366/
11. Froese, D. S., Fowler, B., & Baumgartner, M. R. (2019). Vitamin B₁₂ , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation. Journal of inherited metabolic disease, 42(4), 673–685. Abstract: https://pubmed.ncbi.nlm.nih.gov/30693532/
12. Zeisel S. (2017). Choline, Other Methyl-Donors and Epigenetics. Nutrients, 9(5), 445. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452175/
13. Gregory, J. F., 3rd, Park, Y., Lamers, Y., Bandyopadhyay, N., Chi, Y. Y., Lee, K., Kim, S., da Silva, V., Hove, N., Ranka, S., Kahveci, T., Muller, K. E., Stevens, R. D., Newgard, C. B., Stacpoole, P. W., & Jones, D. P. (2013). Metabolomic analysis reveals extended metabolic consequences of marginal vitamin B-6 deficiency in healthy human subjects. PloS one, 8(6), e63544. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679127/