Methylation part 3: glycine for the win!

In which we discuss how glycine is critical for balancing methylation and optimal health.

This article will be part 3 of my methylation series and also part one of two on glycine. Here we cover the biochemistry of methylation and how glycine plays a pivotal role. Part two will cover the glycine deficiency epidemic created by our modern diets and how to easily correct it, and to explore more aspects of its role in human physiology.

Introduction: review of protein synthesis, introduction to amino acids, description of glycine:

Glycine is the smallest of the amino acids. These are the essential building blocks of the proteins that make up every single tissue of your body, from brains to muscles to red blood cells. These amino acids are linked together following instructions from our DNA to form proteins. DNA has three bases: adenine, cytosine, and guanine. RNA has one other, uracil. These bases are combined in various groups called codons that represent one of the 22 amino acids in human physiology. The nucleus of the cell spits out DNA with a certain codon pattern, which in turn is transcribed onto RNA, which in turn is translated by ribosomes in the cytosol to assemble the long chains of amino acids, called polypeptide chains, that are then folded into proteins. These proteins can be very small and simple such as enzymes like MTHRF or they can be combined to make vast complex structures like muscles, fingernails, hair, or brain cells. Since every cell in our body is replaced every few years there is constant turnover and demand for amino acids from our diet to keep all of the critical tissues, enzymes and organs functioning optimally.

Amino acids are also used to make peptides. Famous peptides you might know are creatine which I have written about extensively in earlier posts, [HERE and HERE] glutathione which is the body’s master antioxidant, and GLP-1, which is the active ingredient in anti-obesity medicines like Wegovy.

There are 22 amino acids that our DNA combines in almost infinite varieties to make the peptides and proteins that comprise your body. You have probably heard about BCAA’s (branch chain amino acids) that the weightlifters consume, or tryptophan in your turkey that makes you sleepy on Thanksgiving. [Actually, it’s not the tryptophan that makes you sleepy, it’s the huge caloric intake of carbs and fat. (1) ]. The smallest and simplest of the aminos is glycine, pictured below. You can see the common features that all amino acids have, the Amine group of H2N, the carboxyl group of COOH, the free hydrogen, and then a side chain of another single hydrogen. It is this side chain consisting of the single hydrogen that makes glycine both so small and unique.

Now take a look at isoleucine (one of the BCAAs) by way of comparison. You can see the same basic features, the Carboxyl group attached to a carbon atom, the amine group (H2n) attached to the same carbon, the free hydrogen on the other side of the amine group, but then in the place of the single hydrogen side chain as in glycine, we see a side chain is much larger and more complex, consisting of a 4 carbon chain boasting two methyl groups (CH3) and one methylene group (CH2)

Due to its simple structure, glycine is considered the most proteogenic of all the amino acids, (meaning it is involved in more protein structures) and it is also both hydrophilic (water-soluble) and lipophilic (fat-soluble) due to the simple hydrogen side chain. This makes it a crucial factor to a surprisingly large number of protein formations and interactions that we could not survive without. The graphic below hits the highlights:

• Glutathione synthesis (the body’s master antioxidant)

• detoxification in the liver by conjugating with toxic substances for excretion

• heme synthesis (can’t make red blood cells without it)

• glucose production and regulating food level intake (surprising link between low glycine levels and obesity/diabetes)

• bile salts which are needed to digest fats

• 100% of the soft tissues in your body that have collagen or elastin-skin, tendons, joints, muscles, ligaments, etc.

Part 2. The role of glycine in methylation:

Let’s focus on the role of glycine in methylation, the other roles will be addressed in part two. (coming soon!) There are two principal roles for glycine in the complex single-carbon transfer system called methylation- the first is to serve as a buffer to maintain a correct ratio of SAMe to SAH. The second is to degrade glycine via the glycine cleavage system (a 4 component reversible enzyme system) into 5,10, methylene tetrahydrofolate (hereafter called 5,10 MTHF) which is the substrate used by the MTHFR enzyme to make SAMe. A substrate refers to the chemical that an enzyme acts on to create a new substance.

To review methylation briefly, you might recall that MTHFR stands for methylene tetrahydrofolate reductase. What MTHFR does is to convert 5,10 methylenetetrahydrofolate into 5,10, methyltetrahhydrofolate. The latter is the compound that donates its methyl group to vitamin b-12, which in turn donates it to SAH ( s-adenosyl homocysteine) and thus completes it’s transformation into SAMe. (s-adenosyl methionine) It is SAMe which in turn circulates in the blood donation its methyl group for so many functions such as neurotransmitter synthesis and dna replication.

However MTHFR can do none of these things without a proper source of 5,10, MTHF which largely is derived from degraded glycine as the graphic below illustrates. (Serine too, but as we shall see later glycine and serine are almost interchangeable and one is often converted into the other) You can see that glycine in green acts on THF, ( tetrahydrofolate from dietary folate in leafy greens or bean) and becomes 5,10 MTHF which is in turn acted on by MTHFR. The result is 5-MTHF which goes to the right of the picture to act on vitamin B12, methylating it. MethylatednB12 then donates its methyl group to SAH and it is now SAMe. (3)

The other function of glycine in the methylation system that we will discuss is to serve as a buffer, maintaining the pool methyl groups by keeping the balance of SAH and SAMe in proper balance. This process of balancing out systems in the body is called homeostasis, and is one of the most important functions of human physiology and metabolism. If you think of how we sweat when hot so as to cool our core temperature down and prevent a heat stroke this is homeostasis in action. Similarly, when the methylation pool is too high, the body achieves homeostasis by transferring a methyl group from SAMe to a glycine molecule to make a new substance called sarcosine. Sarcosine is nothing more than methylated glycine.

Take a minute to look at the graphic above. You can see ‘SAM’ in a yellow box on the upper right, which is another way of saying SAMe. The gray line shows it interacting with glycine, pictured in the green circle again. The end result is sarcosine (methylated glycine) and SAH which can be recycled by MTFHR back into SAMe. Now, you may also notice that the circle on the right continues to a blue box labeled MT, which stands for methyltransferases, of which there are at least 200, and the job of these enzymes is to transfer methyl groups to DNA and neurotransmitters or anywhere else they are needed. [sidebar-the greatest need for methylation is in pregnancy due to all the DNA replication required to grow the baby] When methyl groups are in excess of what is needed they are funneled to glycine, to be stored as sarcosine.

Sarcosine is very interesting in that it has no function in the body other than as a storage depot for methyl groups. You will notice next to sarcosine is a box labeled DMG, which stands for dimethylglycine. This is simply sarcosine with another methyl group added. Also pictured is a substance called betaine (pronounced beet-ah-een) which is also called trimethylglycine. It is simply dimethylglycine with another methyl group added. Betaine can be used by an enzyme called BHMT which I wrote about in my choline article HERE to provide methyl groups in addition to MTFHR as an alternate methylation pathway. Choline also can be degraded into betaine, which in turn can be degraded into dimethylglycine and sarcosine and eventually back into glycine and formaldehyde. (3)

Part 3: Tying it together.

We can see from the above the unified strategy of the body to achieve homeostasis of the methyl pool using glycine. We saw how glycine participated directly in methylation through the glycine cleavage system which produced the grist for the methylation mill that is the MTHFR enzyme. I haven’t mentioned yet that the glycine cleavage system can work in reverse, in which case it is called glycine synthase, and the end result is more glycine. We also saw how glycine uniquely is able to absorb excess methyl groups through the formation of sarcosine where they can be stored for later or excreted from the body.

So what? What’s the big deal? Why should we care about this obscure biochemical process? The reason is that it has profound effects on our physical and mental health. I have known many clients and members of online health groups who have very severe consequences of having MTHFR snps. It often underlies their chronic fatigue, anxiety, depression, or unexplained malaise and migraines. If their doctor was hip enough to run a DNa test and observed the MTHFR SNPs, they are advised to take methylfolate and/or methylb12 in very high dose, which is sounds good in theory and may in fact be all some folks need. But many folks feel much worse on large doses of methylated b vitamins, and some can not tolerate even tiny doses of them. My theory is that they are shunted into overmethylation with these nutrients and have many side effects such as anxiety, headaches, malaise, or jittery feelings.

This is compounded by our modern diets which have a lot of muscle meat and eggs which are high in the amino acid methionine. You might recall that SAMe stands for s-adenosyl methionine and this amino acid is what is methylated to make SAM and is the substrate for MTHFR. When we consume a lot of this amino acid plus take high dose of b vitamins some people over methylate and cannot tolerate it. My guess is that these clients have diets deficient in glycine (ie collagen foods) and/or also have SNPs in the enzyme that makes glycine from the amino acid serine (SHMT-serine hydroxymethyltranferase) and aren’t able to buffer the excess methylation. The average person can make about 2.5 grams of glycine per day from serine and gets about 2.5 more from food this is woefully inadequate. It is estimated it takes 12 grams alone to make the collagen our body’s require for repair every day not to mention the other needs for glycine that use up the pool. (2) So it should come as no surprise that so many people’s methylation is out of balance due to lack of this nutrient which is in such demand by the body.

My preferred approach to supporting MTHFR is to start with creatine and dietary choline as I wrote about in my earlier article. This relieves so much of the burden on methylation system and also supported it directly in a gentler way than with high-dose b vitamins. I also like to recommend adequate sources of glycine in the diet to further support methylation in the ways discussed in part two above. After all, our ancestors for millions of years and even our more recent ones up until 100 years ago ate diets pretty high in these nutrients, as they ate nose to tail and didn’t waste a single part of the animal, including hooves, feet, tendons, joints, skin, and bones. Indeed this is what poorer people always are while richer people alone could afford methionine heavy muscle meats.

This is not to say I’m not in favor of high protein diets, as this is how I have eaten myself for the last ten years. Nor is it to say I’m not in favor of taking methyl folate or b12 which can be magical for many people and I also take myself and recommend to MTHFR clients and will be writing about extensively. What I am saying, is that we must consume glycine containing foods like the ones I listed above, or supplement the diet with collagen and/or glycine to achieve balance and homeostasis. When you consider the huge list of critical bodily processes that require glycine (methylation is only one such process) than you can see why our bodies are crying out for this key nutrient. It might be the doorway for you my dear reader, to less anxiety, better skin, healthier joints, better sleep, and enhanced overall well being.

I hope this inspires you to seek out more glycine in your diet. Part two coming soon will have all the details of how to eat more, and supplement more, and also cover glycine’s role in human collagen and glutathione synthesis and the many implications this has for our health. As always, thank you for reading and sharing this newsletter. Please subscribe and suppor my mission to provide life-changing information to the countless millions of people who would like to enjoy greater mental and physical wellness.

All the best on your journey to better health!

• Disclaimer: I am not a medical doctor. The information in this article does not constitute medical advice and is not intended to diagnose or treat a disease. Readers, especially those who are pregnant or lactating, should speak with their personal medical professional before acting on any of the information discussed

References:

1. https://health.clevelandclinic.org/does-thanksgiving-dinner-make-you-tired accessed 11-18-2024

2. Alves, A., Bassot, A., Bulteau, A.-L., Pirola, L., & Morio, B. (2019). Glycine metabolism and its alterations in obesity and metabolic diseases. Nutrients, 11(6), 1356. https://doi.org/10.3390/nu11061356

3. Zigmund Luka, S. Harvey Mudd, Conrad Wagner,Glycine N-Methyltransferase and Regulation of S-Adenosylmethionine Levels*,Journal of Biological Chemistry,Volume 284, Issue 34,2009,Pages 22507-22511,ISSN 0021-9258,https://doi.org/10.1074/jbc.R109.019273.