Methylation Part 1: A Balancing Act

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The term methylation is tossed around so regularly these days, but what does it really mean?  And how does it affect you?

Many of my health coaching clients have a problem with this and about 40% of the population has a methylation genetic variant.  However, there are some common misconceptions and associations that need to be corrected.  For example, the terms MTHFR and methylation are sometimes used interchangeably, but there is a big difference.  For instance, MTHFR is not just a gene, but also an enzyme.

Methylation is a complex topic, but I want to attempt to give you the “cliff notes” version with just enough detail. 

Disclaimer: I am not a biochemical engineer, so I can’t go too deep! If you are looking for more details, I recommend buying the book Dirty Genes.

What is Methylation vs MTHFR?

Methylation: First off let's define what methylation is.  Technically speaking methylation involves the transferring of a methyl group, which is one carbon and three hydrogen atoms that act upon different types of molecules (such as enzymes, hormones, neurotransmitters, genes, etc.).

The way I like to think about methylation is that it is a series of cycles that are ever processing these methyl groups.  One step or process relies on the other so there is an interdependency between them.  If one cycle or process is not performing optimally then it will or can affect the others.

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MTHFR: is an enzyme that methlates folate (B9) and converts it to methylfolate.

Research indicates that at least 45% of people have an MTHFR gene mutation and they consequently have a decreased ability to turn folic acid into folate (the process doesn’t completely stop; it merely decreases by 40 to 80%).

If you have an MTHFR gene mutation, your body is less able to use folic acid in the methylation cycle.  This can have in impact on the methylation cycle as you will see in a bit.

Before we get into a description of the cycle(s), here are the main enzymes that are involved in the methylation cycle and what they do:

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Methylation in a nutshell:

Here are the main cycles that are involved with methylation. See diagram below for more details.

1. Folate Cycle:  this is where the MTHFR enzyme is involved.  It takes folic acid and converts it to methylfolate.  Methylfolate is the active form of folate that your body can use.  As you can see in the diagram below, the Folate cycle intersects with the Methionine cycle.  The methylfolate then works with MTR and that interacts with MTRR in the Methionine cycle, which is explained next.


2. Methionine Cycle: during this cycle methionine is used to create S-Adenosyl Methionine (SAMe). SAMe powers over 200 enzymes necessary for healthy cell growth, maturation, and specialization. While MTHFR is always thought to be central in methylation it is actually SAMe that that is the star of the show. SAMe is the body's main methyl donor and is what helps the rest of the body methylate. [ii]


Sometimes SAMe helps your body to create and use new compounds and sometimes it can help your body breakdown and expel other compounds.  Examples of new compounds: phosphatidylcholine, creatinine and melatonin.  Examples of compounds it breaks down: arsenic, histamine and estrogen.

Afterwards, SAMe gets recycled and continues on in the cycle and converts into homocysteine.  Homocysteine is the end product of methylation as well as the beginning of the next one. You probably have heard of homocysteine and that too much of it is associated with an increased risk of strokes and cardiovascular disease.  

However, you do need some of it to help with the conversion through the MTR/MTRR and then back into Methionine. MTRR creates methylcobalamin (a form of vitamin B12) and then MTR uses that methylcobalamin, together with methylfolate (the methylfolate we just spoke about), to turn a substance called homocysteine into another, which is methionine. [iii]

Another pathway back to methionine is through the BHMT pathway. BHMT is 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 make methionine, which is (again) turned into SAMe by the MAT enzyme.[iv] This is not the optimal pathway.  This may work in the short-term, but can’t support the whole body.

The last pathway for homocysteine is that it can pass through the Transsulfuration cycle, which is the next cycle

3. Transsulfuration Cycle: Working with the CBS enzyme, homocysteine helps create the most important antioxidant - glutathione. CBS acts as a built-in ‘drain’ by removing homocysteine and using it to process ammonia and make glutathione. [v]

If your body has free radicals/oxidative stress, you need more glutathione to detox and your body will shuttle the homocysteine into this cycle to help make it.  In that case, you may be skimping on making more SAMe.

Figure 1: Methylation Cycle

Figure 1: Methylation Cycle

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Since the cycles are all interdependent it is understandable how some people have merged the importance of the MTHFR gene with the methylation cycle as a whole. While it is true that if you do not have enough methylfolate you will impact your body's ability to make methionine,  homocysteine  and the SAMe, but importance needs to be placed on the whole cycle so that you ensure you're producing enough SAMe and glutathione.

Impact of Poor Methylation:

If you have issues anywhere within the methylation cycle it can seriously impact your overall health.  More specifically it can have a negative effect on:

·        Genetic expression and repair

·        Energy Production

·        Cellular protection

·        Brain and muscle health

·        Neurotransmitter Production

·        Detoxification

·        Immune response

·        Cardiovascular function

·        Stress and relaxation responses[vi]

Next month we will go into more detail of how you can make sure your methylation is on point and some strategies on how you can help yourself.








Julie Kenney