M is for Methylation, how to use genetic clues

Methylation involves the transfer of a small molecule, similar in size to H2O, containing one carbon and four hydrogens. The availability and transfer of that little methyl molecule is an incredible contributor to many of the biochemical pathways integral to the function of human life. Methylation plays a significant role in regulating homocysteine levels, stabilizing epigenetics, potentially silencing oncogenes, supporting phase II liver detoxification, and modulating aging.

The methylation cycle is composed mainly of the methionine and folate cycles. The integration of these two pathways leads to the greatest contribution of methyl donors also referred to as one-carbon donors. One-carbon metabolism, also known as methylation, is responsible for donating methyl groups that synthesize DNA, RNA, creatine, choline, carnitine, Coenzyme-Q10, melatonin and myelin basic proteins. Methylation is necessary to repair proteins, metabolize niacin, estrogen, xenobiotics and catecholamines. Methylation inactivates histamine and activates phospholipids that keep our cell membranes fluid, among many other important jobs. Additionally, methyl groups play a key role in modulating immunity by supporting the production of natural killer cells and T cells.

Numerous prevalent genetic single nucleotide polymorphisms (SNPs) are utilized in these pathways. Some of the most relevant SNPs in the methylation cycle include methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase and cystathionine beta-synthase (which links the methionine and transulfuration cycles). Polymorphisms in the genes that encode for these enzymes may result in shifting the rate of transformation in the folate and methionine cycles. This in turn will affect the availability of methyl, or one-carbon, donors from SAMe.

This information will be outlined and explained in further detail at the Kashi Core Training Workshop in Medical Genetics on July 21, 2018. In addition, there are three more components that we will be explored during the training: the biopterin, transulfuration and urea cycles, all of which cross paths with the methionine and folate cycles directly and indirectly. The Biopterin cycle requires balanced movement of folate via the methylenetetrahydrofolate reductase enzyme through the folate cycle in order to convert dihydrobiopterin to tetrahydrobiopterin. Tetrahydrobiopterin is a cofactor for the creation of aromatic amino-acid hydroxylases. Aromatic amino-acid hydroxylases are necessary pieces of the neurotransmitter production puzzle. Dopamine, norepinephrine, epinephrine, serotonin and trace amine levels are all reliant on a stable biopterin cycle. The rate of neurotransmitter metabolism links the biopterin cycle to COMT and MAOA, both referred to as the warrior genes. These SNPs will be explored in the lecture on Graceful Aging.

Tetrahydrobiopterin is a cofactor in the urea cycle which breaks down ammonia and produces nitric oxide. This is how the urea cycle can feedback into the methylation cycle through SNP mutations or vice-versa. When the Urea cycle is not optimally functioning, the result is elevated peroxynitrate and super oxide which cause neuronal damage, microglial activation and an overall increase in oxidative stress. Nitric oxide synthase is one of the prominent single nucleotide polymorphisms featured in the urea cycle.


Cystathionine beta-synthase (CBS) links the methionine and transulfuration cycles through the conversion of homocysteine to cystathionine. The transulfuration cycle is an integral part of the production of our bodies master, intracellular, anti-oxidant, glutathione, as well as, the calming amino acid taurine, which is also a bile pre-cursor. Improper function of the transulfuration cycle can result in increased production of toxic ammonia and sulfites.

Together this community of biochemical pathways play an enormous role in an individuals health. Not only we will be discussing the basic pathways function and interactions, but what makes them function more and less effectively, what pathologies they are associated with according to the most recent research, what to do about the single nucleotide polymorphisms, and side-effects to watch out for based the multiple nutrient supplements required.