Glycine

Glycine is the smallest of the 20 amino acids, and unlike the other amino acids, it does not have a significant side chain, allowing it to act as a flexible link for specific proteins by connecting protein domains together.¹ This makes glycine a common feature in amino acid motifs at protein active sites.² Its prominence in protein structure explains why it represents 11.5% of total amino acid content in the human body.³

Glycine biosynthesis can take place through three pathways.⁴ The first occurs via the amino acid serine, which is produced from D-3-phosphoglycerate, a glycolysis intermediate. It can also be produced from threonine with threonine dehydrogenase and 2-amino-3-ketobutyrate lyase. Oxidative degradation also helps synthesize glycine from choline. Finally, glycine can be produced from glyoxylate through transamination with alanine.

Glycine metabolism also occurs through three distinctive mechanisms.⁴ First, it can be metabolized through the glycine cleavage system, a complex enzyme system that conducts the reversible reaction at the last step of producing glycine from serine.⁵ Serine hydroxymethyltransferase, the enzyme that catalyzes glycine synthesis from serine, also catalyzes serine formation from glycine.⁴ Finally, D-amino acid oxidases can convert glycine into glyoxylate.

Although humans can synthesize glycine, we still require dietary supplementation (usually from meat and dairy products) to support normal bodily functions, making it one of the conditionally essential amino acids. It is absorbed in the small intestine and enters the circulation, from whence it can provide a range of benefits.⁶

Glycine and Muscles

Glycine is a major component of collagen. Collagen is primarily composed of amino acids occurring as the following motifs: glycine-proline-X or glycine-X-hydroxyproline. Because collagen holds together skin, cartilage, and other body structures together, insufficient glycine synthesis is associated with weak muscles and inadequate amounts of protein for maintaining homeostasis—clinical studies show that lower plasma glycine levels correlate with lower metabolic capacity.⁷ Glycine supplementation has been shown to protect muscles from several disease states, such as sepsis and cancer cachexia, that lead to muscle degradation.⁸

Glycine and the Central Nervous System

Glycine is also a neurotransmitter, binding to glycine receptors most commonly found on postsynaptic neurons,⁹ many of which are located in the spinal cord.¹⁰ The reduced activity of these receptors can cause people to be more sensitive to pain and noxious smells.¹¹ Therefore, potentiating glycine receptor activity may be a viable approach to treat chronic pain. In turn, the amino acid’s inhibitory activity has encouraged research to determine whether selectively activating those receptors can alleviate chronic pain.¹²

Glycine and Oxidative Stress

Current research also shows that glycine supplementation protects against oxidative damage by increasing levels of glutathione, an antioxidant that reduces the harmful effects of oxidative stress by reducing free radicals.¹³ Glycine’s ability to protect animals from oxidative stress has encouraged farmers to introduce it as a supplement in animal feeds.¹⁴ A recent randomized controlled clinical trial also showed that glycine and dietary cysteine supplementation increases glutathione levels at a dose-dependent rate.¹⁵

Glycine and Liver Function

Glycine may also improve liver health and function. In male Wistar rat models of alcohol-induced liver damage, glycine supplementation alleviated damage from alcohol-induced liver injury.¹⁶ Another study demonstrated increased fatty acid oxidation and increased glutathione synthesis in the livers of mice with non-alcohol-induced liver injury.¹⁷ These results demonstrate that glycine acts on the liver, protecting it from long-term damage.

Glycine and Stroke

Despite the myriad beneficial effects that glycine confers, glycine intake has been linked with ischemic stroke. A large cross-sectional study of Japanese adults showed that a higher intake of glycine was associated with an increased risk of mortality from total and ischemic stroke.¹⁸ Conversely, other case-control studies note a reduced risk of ischemic stroke with higher levels of glycine.¹⁷ Furthermore, glycine supplementation provides a protective effect against ischemia-reperfusion injury in the small intestines and the liver.³ More research is needed to fully understand the relationship between glycine and stroke.

Glycine Supplementation

Given its wide range of physiological functions, glycine is an important molecule in clinical nutrition. For example, high doses of glycine have been shown to enhance collagen synthesis among chondrocytes, the body’s main collagen producers.¹⁹ Glycine is also required along with the amino acids methionine and arginine to produce the amino acid creatine.²⁰ Like collagen, creatine is mostly found in muscle tissue. Adequate levels of creatine increase ATP production, providing energy to maintain high-intensity exercise.²¹ People eager to improve their fitness can also take glycine supplements during their workout routines. In exercise routines, glycine supplementation increases muscle endurance and reduces fatigue during high-intensity training.²²

Glycine in Research

As of August 2023, there are nearly 6,000 citations for “glycine” in research publications (*excluding books and documents) on PubMed. Because many of these publications link glycine to a wide range of health and disease states, any study aiming to advance our understanding of human physiology may benefit from measuring glycine concentrations. Additionally, glycine’s nutritional value and its role in muscle health and recovery suggest that glycine quantification would be a great addition to any nutrition and exercise science research program.

References

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2. Yan BX, Sun YQ. Glycine Residues Provide Flexibility for Enzyme Active Sites*. J Biol Chem 1997;272(6):3190-3194. doi:10.1074/jbc.272.6.3190
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5. Kikuchi G, Motokawa Y, Yoshida T, Hiraga K. Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proc Jpn Acad Ser B Phys Biol Sci 2008;84(7):246-263. doi:10.2183/pjab/84.246
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9. Stephan J, Friauf E. Functional analysis of the inhibitory neurotransmitter transporters GlyT1, GAT-1, and GAT-3 in astrocytes of the lateral superior olive. Glia 2014;62(12):1992-2003. doi:10.1002/glia.22720
10. Zeilhofer HU, Werynska K, Gingras J, Yévenes GE. Glycine Receptors in Spinal Nociceptive Control—An Update. Biomolecules 2021;11(6):846. doi:10.3390/biom11060846
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13. Wang W, Wu Z, Lin G, et al. Glycine Stimulates Protein Synthesis and Inhibits Oxidative Stress in Pig Small Intestinal Epithelial Cells. J Nutr 2014;144(10):1540-1548. doi:10.3945/jn.114.194001
14. Siegert W, Rodehutscord M. The relevance of glycine and serine in poultry nutrition: a review. Br Poult Sci 2019;60(5):579-588. doi:10.1080/00071668.2019.1622081
15. Lizzo G, Migliavacca E, Lamers D, et al. A Randomized Controlled Clinical Trial in Healthy Older Adults to Determine Efficacy of Glycine and N-Acetylcysteine Supplementation on Glutathione Redox Status and Oxidative Damage. Front Aging 2022;3:852569.
16. Iimuro Y, Bradford BU, Forman DT, Thurman RG. Glycine prevents alcohol-induced liver injury by decreasing alcohol in the rat stomach. Gastroenterology. 1996;110(5):1536-1542. doi:10.1053/gast.1996.v110.pm8613061
17. Rom O, Liu Y, Liu Z, et al. Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome. Sci Transl Med 2020;12(572):eaaz2841. doi:10.1126/scitranslmed.aaz2841
18. Nagata C, Wada K, Tamura T, et al. Dietary Intakes of Glutamic Acid and Glycine Are Associated with Stroke Mortality in Japanese Adults1,2. The J Nutr 2015;145(4):720-728. doi:10.3945/jn.114.201293
19. de Paz-Lugo P, Lupiáñez JA, Meléndez-Hevia E. High glycine concentration increases collagen synthesis by articular chondrocytes in vitro: acute glycine deficiency could be an important cause of osteoarthritis. Amino Acids 2018;50(10):1357-1365. doi:10.1007/s00726-018-2611-x
20. Casey A, Greenhaff PL. Does dietary creatine supplementation play a role in skeletal muscle metabolism and performance? Am J Clin Nutr 2000;72(2 Suppl):607S-17S. doi:10.1093/ajcn/72.2.607S
21. Clark JF. Creatine and Phosphocreatine: A Review of Their Use in Exercise and Sport. J Athl Train 1997;32(1):45-51.
22. Stevens BR. Chapter 54 – The Role of Glycine-Arginine-Alpha-Ketoisocaproic Acid in Sports Nutrition. In: Bagchi D, Nair S, Sen CK, eds. Nutrition and Enhanced Sports Performance (Second Edition). Academic Press; 2019:637-644. doi:10.1016/B978-0-12-813922-6.00054-0