Methylation Part 1: Creatine, MTHFR, and metabolism.

Introducing creatine’s role in energy metabolism and the methylation cycle.

Introduction: 

I am very excited to share with my readers the research I have been doing on creatine, which has become so significant for my health as well as that of my family and clients. To make a long story short, creatine is a simple amino acid vital to human energy metabolism. Its principal role is to recycle and buffer ATP, the molecule produced in the mitochondria that fuels every function in the human body. ATP stands for adenosine triphosphate and it’s made in almost every cell and powers the activity of the cell.  When it loses phosphorus in such activity, for example, helping a muscle to move or a neuron in the brain to fire, it becomes ADP-adenosine diphosphate (ADP). When it loses another it becomes adenosine monophosphate (AMP). It then needs to be recharged by adding phosphorus or the cells will run out of energy. ATP is constantly being generated through glycolysis and the Krebs cycle, also known as anaerobic and aerobic respiration respectively, but these processes take time. Creatine plays a critical role as a buffer and donor of phosphorus back to ADP (or AMP) which regenerates it back to ATP far quicker than glycolysis and the Krebs cycle. This process happens constantly with creatine demand increasing dramatically in muscle tissue during times of high exercise and also in the brain which uses up 20% of the body’s ATP production even though it only contains 2% of the body’s weight. Creatine also buffers excess ATP production during a sedentary period and in this reaction, creatine is turned into phosphocreatine by the addition of phosphorus donated by the unused ATP. This allows the cell to have a readily available source of phosphorus for when you suddenly spring into action, like leaping up off the couch after a long sit.

The graphic below illustrates this process wherein phosphocreatine donates its phosphorus to ADP resulting in creatine and ATP, and more power available for the work the cell involved needs to do. It also shows how this reaction is reversible and how ATP excess which occurs when the body is at rest, will give its phosphorous back to creatine to make phosphocreatine, storing it for future use when the body is back in motion. 

ATP, and therefore creatine, is required in every cell to work properly. How intense is this process of constant ATP use and regeneration by creatine? Consider that the the average human makes over 100 lbs (50 kilos) of ATP per day, and uses up 10,0000 molecules of ATP per second. (2) ATP must be recycled by creatine, which is also constantly being generated in most cells, particularly the skeletal muscle and the brain, and without an adequate supply of creatine, the constant turnover of ATP use and recycling will not properly occur, and certain cells may be starved for energy and not function optimally. 

Why would someone not have enough creatine?

It is no wonder then that genetic polymorphisms in the two enzymes that produce creatine and the one that transports it ( guanidinoacetate methyltransferase, glycine amidinotransferase, and CRTR for those who would enjoy further research) lead to creatine imbalance, collectively called Creatine Deficiency Disorders, are so devastating with consequences such as; developmental delays, language delays, hypotonia, seizures, epilepsy, behavior disorders, ASD, ADHD-like symptoms, movement disorders, and more. (3) These very severe creatine deficiency disorders are thankfully quite rare. But readers might recall how in my introduction to vitamin C and the common cold( read the article here), I observed that true scurvy was quite rare. However, mild vitamin C deficiency was all but ubiquitous, a condition we call subclinical scurvy, and this was still problematic. Similarly, mild creatine deficiency is also quite common due mainly to three factors:

1. Mild versions of the genetic SNP’s mentioned above

2. A diet that is insufficient in creatine due to lack of access to high-creatine foods, or by choices such as self-imposing limits on meat and fish. 

3. Excessive physical or mental stress creating a temporary shortage.

Methylation and creatine

Let’s break this down a little further and discuss how methylation fits in. Creatine levels are sustained mostly by endogenous production, which requires the functioning of the enzymes I mentioned above, plus the amino acids glycine, and arginine. One of these enzymes, glycine amidinotransferase (GAMT) requires methylation by SAMe, which is the end product of the methylation cycle. Without GAMT receiving a methyl group from SAMe, creatine can NOT be synthesized. I’m going to be writing a lot about methylation in this newsletter, and have chosen to talk about creatine by way of introduction to this critical process, as creatine synthesis accounts for 45-70% of a person’s entire output of SAMe, which is the principle methyl donor in the body for a great many critical purposes. (1)  

What is methylation and why is it important?

Methylation in a nutshell means the transfer of a single carbon atom bound to 3 hydrogens in what is called a methyl group from one molecule to another. This process is critical for so many functions in the human body. For example, liver detox, cellular replication, DNA repair, protein function, and gene replication all require methylation. So does the manufacture of neurotransmitters such as dopamine and serotonin which are so critical for mental health and mood regulation. 

As many as 70% or more of people have genetics that impair the methylation process. Readers might be familiar with the enzyme called MTHFR which transfers a methyl group from the essential (meaning we only get it from diet) amino acid methionine using folate and vitamin b12. A SNP (single nucleotide polymorphism) on the gene for this enzyme means that this process will occur less efficiently, than in someone who does not have this SNP. The two genes most affected are referred to as A1298C and C677t and one can be homozygous in either one of them or in both of them, meaning that you inherited two copies of the gene variation from each parent. Or you can be heterozygous in one of the genes or both, meaning that you inherited one copy of each gene from each parent. If one of these genes is heterozygous it could potentially reduce the rate of methylation by 30%, or not at all, depending on other genetic factors. Generally speaking, being dual heterozygous in both MTHFR genes or homozygous in one has the potential to reduce methylation rates up to 60% or even 70% (5)

Take a look at the chart above. You can see the MTHFR enzyme in the lower left corner. Its role is to convert 5,10, methylene tetrahydrofolate to 5-methyl tetrahydrofolate, which in turn is capable of donating the methyl group to vitamin b12, which in turn donates it to methionine, thus creating SAMe in the process and preventing a toxic buildup of homocysteine. You can see there are many other enzymes involved in this process; MTR, methione synthase which converts homocysteine to methionine, and MTRR which recycles vitamin b-12 so it can be reused. Then there is BHMT which is an alternate pathway for creating SAMe from betaine and then the family of methyl transferases such as COMT, which you may have heard of, which are so critical in dopamine and estrogen metabolism. Lastly, there is the CBS enzyme (cystathione beta syntase) which takes homocysteine and transforms it into glutathione, the body’s master antioxidant. We will do a much deeper dive into methylation, and the critical roles of folate and b-12 and glutathione in future articles and won’t go any deeper into these enzymes here. My purpose for showing you this graphic was to highlight the amazing complexity of this critical metabolic pathway and stress that it’s possible to have SNP’s on any one of these enzymes, or some or even all of them, and that this will slow down the efficiency of this cycle, which means that the body will be under stress trying to keep up with creatine production. A simple functional test for methylation is a blood test for homocysteine, which will accumulate if MTHFR is not functioning well enough to facilitate its transformation into SAMe. Accumulation of homocysteine is strongly indicated as a risk factor in heart disease. There are more comprehensive tests that functional nutritionists like myself can use such as Genova Labs Methylation panel or Stratagene to help you understand how methylation works in your body.

How does creatine fit in with methylation and mental health?

 Since creatine is necessary for ATP production and survival, the body will prioritize its methylation capacity to manufacture creatine in favor of other important things that are not as critical to survival, such as making dopamine or serotonin. There is increasing evidence this is often at the cost of mental health. (4) Indeed a 1988 study found a positive relationship between cerebral spinal fluid levels of dopamine and serotonin metabolites and creatine and creatinine levels (1). Positive in this context means clearly linked, ie, patients with higher creatine had high levels of the neurotransmitters, and those with lower levels of creatine had lower levels of the transmitters, which makes a case for proper neurotransmitter function being affected by creatine status in the brain. 

Furthermore, creatine metabolism in mental health has been studied using neuroimaging studies such as MRI and PET scans. Scientists have studied the brains of healthy controls, and compared their creatine levels using these scans with patients suffering from various mental illnesses and found some striking correlations between low levels of creatine in various structures of the brain in patients with depression, anxiety, schizophrenia, and PTSD. (1) From this we can understand that reduced creatine levels in the brain are associated with various mental and nervous disorders.

Review:

1. Creatine is an essential function of the mitochondrial energy system that makes life possible 

2. It is depleted in times of high exercise or stress in both muscle tissue and brain tissue 

3. Its manufacture is completely dependent on the methylation system. 

4. The methylation system may be impaired in many individuals due to genetic SNPs in any of the genes that synthesize the enzymes involved such as MTFHR C677T.

5.  This in turn can lead to reduced levels of neurotransmitters in the brain 

6. This could lead to negative mental health and neurological outcomes 

Whew! We have covered a lot of ground and this is enough for one article. Part two will be released in a few days. It will cover recent research using creatine as a treatment for various mental health and neurological disorders, as well as detailed instructions on how to attain optimal levels of creatine from both diet and supplementation. As always thank you for reading, and sharing this newsletter with your friends and family, and supporting my mission to provide life-changing information to the countless millions of people who would like to enjoy greater mental and physical wellness. 

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 an illness or disease. Rather this newsletter is for informational, educational, and entertainment purposes. Readers should consult with their personal medical professional before acting on any of the information discussed.

References: 

1.    Allen, P. J. (2012). Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value? Neuroscience and Biobehavioral Reviews, 36(5), 1442–1462. doi: 10.1016/j.neubiorev.2012.03.005

2. National Center for Biotechnology Information (NCBI).Physiology, Adenosine Triphosphate Jacob Dunn; Michael H. Grider. Accessed 6-27-2024 https://www.ncbi.nlm.nih.gov/books/NBK553175/ 

3.Mercimek-Andrews, S., & Salomons, G. S. (n.d.). Creatine Deficiency Disorders. https://www.ncbi.nlm.nih.gov/books/NBK3794/#:~:text=The%20creatine%20deficiency%20disorders accessed 6-27-24

4. Menezo, Y., Clement, P., Clement, A., & Elder, K. (2020). Methylation: An Ineluctable Biochemical and Physiological Process Essential to the Transmission of Life. International Journal of Molecular Sciences, 21(23), 9311

5. Korovljev, D., Todorovic, N., Stajer, V. et al.Temporal trends in dietary creatine intake from 1999 to 2018: an ecological study with 89,161 participants. J Int Soc Sports Nutr 18, 53 (2021). https://doi.org/10.1186/s12970-021-00453-1