Methylation

All Things Methylation

Introduction

Methylation is a term that is thrown around a lot in the functional medicine world. Heart disease, autism, Alzheimer’s and many other diseases have been linked to methylation problems. When most bloggers and functional doctors talk about methylation, they mean the process of the methylation cycle.

DISCLAIMER: I am not a doctor, or medical researcher, although I spent 3.5 years in pharmacy school so I’m game to go down the rabbit holes. ;-) This is my digest of the methylation research that I have read over the past few years.

So, here’s what I’ve dug up, which is certainly not all-encompassing. I’ve added a handful of studies to illustrate specific points, but rest assured, there are many more studies to read. And do feel free to add your interpretations or pass along your research results.

Methylation Cycle (aka One Carbon Cycle)

The methylation cycle’s main function is to convert methionine from the diet (eggs, meat, fish, brazil nuts and some seeds) to SAM (S-adenosylmethionine, also known as AdoMet, SAM-e). SAM is the primary active methyl donor in the body. If some process needs a methyl group, SAM is the man. Most SAM is produced and used in the liver.

This cycle supplies methyl groups, consisting of one carbon and three hydrogens (aka CH3), for a large number of methylation reactions, including those that methylate (and turn “off”) DNA, and processes involved in creating a wide variety of substances, including creatine, choline, carnitine, coenzyme Q-10, melatonin and myelin basic protein. Methylation is also used to metabolize dopamine, norepinephrine and epinephrine, to inactivate histamine, and to methylate phospholipids, promoting the integrity of and transmission of signals through cell membranes.

One study found 208 proteins that make up the human “methyltransferasome,” or those proteins that act as enzymes that transfer a methyl group from SAM. Those proteins represent only about 0.9% of all human gene products. However, 30% of those enzymes that transfer a methyl group, called methyltransferases, are associated with disease, most frequently cancer and mental disorders. These methytransferases include several well-known to the APOE4 forum including COMT, PEMT, HNMT and BHMT. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013446/)

Methylation is so fundamental to every cell, that it is estimated to take place more than a billion times per second. Yep, it’s that important.

See also: http://ajcn.nutrition.org/content/76/5/1151S.full http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405985/

Once a methyl group transfer takes place, you are left with SAH (S-adenocyl homocysteine). The body is pretty efficient at recycling, so SAH gets recycled by an enzyme to create homocysteine and adenosine. From there, homocysteine is recycled back to methionine through transfer of a methyl group from the active form of folate, specifically 5-methyltetrahydrofolate (also known as 5-MTHF, L-methylfolate and other names). This is accomplished by one of the two paths.

• The first path uses the MTR gene and requires B12.
• The second path, found in the liver and kidney, is encoded by the BHMT gene, which transfers a methyl group to homocysteine from betaine (also known as trimethylglycine or TMG). Zinc is a cofactor.

In either path, methionine is then converted back to SAM, completing the cycle.

Now the body has other ways to keep this important cycle working well. When methylation is compromised, plasma homocysteine levels rise, increasing oxidative stress and the rate at which glutathione stores are depleted. If high homocysteine becomes chronic, BHMT and MTR enzymes are down-regulated and homocysteine is sent down the transsulfuration pathway. In this pathway, homocysteine is irreversibly converted to cystathionine by an enzyme created by the CBS gene, which requires the cofactor vitamin B6. The resulting byproduct, cysteine can be utilized in a number of cellular functions, including glutathione (GSH) production and protein synthesis. But in high homocysteine, with it’s increase in oxidative stress, the body focuses on increasing glutathione to battle the oxidative stress.

So the dance between these various pathways is a delicate one, where lots of things can go awry. Instead of typing a lot more on how methylation works, this picture is worth more than a thousand words.

PLEASE DO NOT SHARE THIS IMAGE OUTSIDE OF THE APOE.INFO SITE, AS IT IS COPYRIGHTED. I purchased the Seeking Health Planner kit, and provide this image as allowed under educational use.