trimethylglycine / TMG
Methylation Panel
Methylation is a biochemical process in which methyl groups (CH3) are transferred or donated between molecules, thereby changing their structure and function. This happens billions of times per second in every cell throughout the body. The methylation cycle is dependent on amino acids, vitamin cofactors, and minerals obtained from the diet to ensure adequate function of this biochemical pathway.
The incredibly vast processes in the body that depend upon methylation are what ultimately make functional testing for methylation impairment a valuable clinical tool. Some of these processes include, but are not limited to:
- creatine production for skeletal muscle contraction
- DNA and RNA synthesis
- gene regulation (epigenetics)
- hormone regulation and detoxification
- energy production
- cell membrane repair
- fat metabolism
- myelination
- immune function
- neurotransmitter production and metabolism
- vascular endothelial function and nitric oxide production
To keep these processes functioning optimally, there is a necessary balance between many different biochemical pathways. What is termed the “methylation cycle” involves an interplay between folate metabolism, methionine metabolism, and homocysteine transsulfuration.
The body continually adapts these interconnected pathways in order to maintain homeostasis.
However, key amino acid deficiencies, a lack of vitamin and mineral cofactors, genetic enzymatic predispositions, and a wide array
of oxidative stressors can impact multiple enzymes leading to a disruption in a patient’s overall methylation status.
Biomarkers in this category
18 biomarkers · optimal ranges shown
associated with metabolic syndrome
a nutrient that supports various bodily functions
a nonessential sulfur-containing amino acid
an intermediate of the transsulfuration pathway
is produced when betaine donates a methyl group to homocysteine
one of the body’s most powerful antioxidants
a nonessential amino acid with many important physiologic functions
a key indicator of methylation status
compares between methylation and transsulfuration pathways
an essential amino acid that plays an important role in the methylation cycle
Novel functional assessment for overall methylation balance
commonly referred to as the “Methylation Index”
SAH is hydrolyzed to homocysteine
Methyl Group Donor
Sarcosine is an amino acid made when SAM is conjugated with glycine by the glycine-N- methyltransferase (GNMT) enzyme. It can also be made by catabolism of DMG. There are many dietary sources of sarcosine including eggs, legumes, nuts, and meats. [L] Sarcosine is also available as an over-the-counter supplement, and it is widely used in cosmetic formulations (toothpaste, creams, and soaps) and detergents. [L] In the methylation cycle, sarcosine is created by the GNMT enzyme, which functions to control SAM excess. Disposal of excess SAM is seen in excess methyl donor supplementation, or SAM elevation due to adiposity/ obesity. Some clinicians use sarcosine elevation as a marker of ‘excess methyl supplementation’ or ‘over- methylation.’ Currently, there is no literature to support this hypothesis, but rather it is based on physiology. [L] Sarcosine can also be produced through the breakdown of DMG. Both sarcosine and dimethylglycine have pharmacological actions in the central nervous system. [L] Sarcosine is a natural glycine transport inhibitor in the CNS, enhancing N-methyl-D-aspartate (NMDA) receptors. NMDA synaptic receptors are not only important for basic CNS functions (breathing, motor function), but also learning, memory, and neuroplasticity. Decreased NMDA function results in cognitive defects, and overstimulation causes excitotoxicity. [L] Abnormalities in these receptors are implicated in many diseases and targeted for pharmacologic therapy. [L] Sarcosine has been shown to be a co-agonist for NMDA receptors. For this reason, there are many studies evaluating sarcosine as an adjunct treatment for psychiatric diseases, such as schizophrenia, which is characterized by decreased NMDA function. In addition, using sarcosine to enhance NMDA function can improve depression-like behaviors. [L] Since DMG is essentially sarcosine with an extra methyl group, research shows that they have similar effects. [L] Some studies have evaluated urinary and serum sarcosine’s use as a prostate cancer progression marker; however, the data is mixed. [L], [L], [L] These studies are based on nonspecific metabolomic profiling, which followed random metabolite elevation patterns. But, as noted, literature is mixed regarding whether this translates to clinical practice. Sarcosine has no known toxicity, as evidenced by the lack of phenotypic expression of inborn errors of sarcosine metabolism. [L] -------------- References: - Strzelecki D, Podgorski M, Kaluzynska O, et al. Supplementation of Antipsychotic Treatment with the Amino Acid Sarcosine Influences Proton Magnetic Resonance Spectroscopy Parameters in Left Frontal White Matter in Patients with Schizophrenia. Nutrients. 2015;7(10):8767-8782. [L] - Luka Z, Mudd SH, Wagner C. Glycine N-methyltransferase and regulation of S-adenosylmethionine levels. J Biol Chem. 2009:jbc. R109. 019273. [L] - Lee M-Y, Lin Y-R, Tu Y-S, Tseng YJ, Chan M-H, Chen H-H. Effects of sarcosine and N, N-dimethylglycine on NMDA receptor-mediated excitatory field potentials. J Biomed Sci. 2017;24(1):18. [L] - Frontiers in Neuroscience. In: Van Dongen AM, ed. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press/Taylor & Francis Taylor & Francis Group, LLC.; 2009. [L] - Kemp JA, McKernan RM. NMDA receptor pathways as drug targets. Nat Neurosci. 2002;5:1039. [L] - Hashimoto K. Glycine transporter inhibitors as therapeutic agents for schizophrenia. Recent Pat CNS Drug Discov. 2006;1(1):43-53. [L] - Lucarelli G, Fanelli M, Larocca AMV, et al. Serum sarcosine increases the accuracy of prostate cancer detection in patients with total serum PSA less than 4.0 ng/ml. Prostate. 2012;72(15):1611-1621. [L] - Jentzmik F, Stephan C, Miller K, et al. Sarcosine in Urine after Digital Rectal Examination Fails as a Marker in Prostate Cancer Detection and Identification of Aggressive Tumours. Eur Urol. 2010;58(1):12-18. [L] - Sreekumar A, Poisson LM, Rajendiran TM, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009;457(7231):910. [L] - Scriver CR, Beaudet AL, Sly WS, et al. Metabolic and Molecular Bases of Inherited Disease, 4 Volume Set. McGraw-Hill Professional Publishing; 2000. [L] - Allen RH, Stabler SP, Lindenbaum J. Serum betaine, N, N-dimethylglycine and N-methylglycine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism. Metabolism. 1993;42(11):1448-1460. [L]
Primarily used in methylation balance calculation
Taurine’s highest concentration is in muscle, platelets, and the central nervous system.