In 1952, Arnstein wrote a review on glycine metabolism.¹ He noted that understanding clearly showed that extremely simple substances are often used for the biosynthesis of many complex molecules found in living organisms and that glycine occupies a central place in animal metabolism. Glycine is a non-essential amino acid synthesized by animals, microorganisms and plants. It is present in most tissues and is a key substance in the metabolism of one-carbon fragments, proteins, peptides, nucleotides, porphyrins and bile salts. Glycine is one of the smallest amino acids. Its small size and lack of a side chain allow it to function as a flexible part in many proteins, thus vitally influencing their function. It consists of a carbon molecule attached to an amino and a carboxyl group.

Fig 1. The chemical structure of glycine. ^10,11 

Beneficial effects of glycine

It is difficult for many to understand that the simplest amino acid, glycine, can achieve beneficial effects in many pathological conditions. It is now clear that dietary glycine, which increases blood glycine concentrations to more than 1 mM from basal concentrations in the range of 0.1 – 0.2 mM, protects against shock caused by blood loss or endotoxin. It reduces the level of alcohol in the stomach and improves recovery from alcoholic hepatitis. It also reduces fibrosis caused by experimental drugs. It reduces liver damage caused by hepatotoxic drugs and blocks programmed cell death. In the kidneys, it reduces nephrotoxicity caused by the drug cyclosporin A and prevents hypoxia and the formation of free radicals. There are many other roles that glycine fulfills:

• Glycine has a cytoprotective effect!

During the last few years, numerous reports have suggested that prophylactic and therapeutic administration of glycine can protect organs and tissues in several pathophysiological conditions (Table 1).

• Glycine provides tissue protection!

There is substantial experimental evidence that free glycine may play a role in tissue protection against insults such as ischemia, hypoxia, and reperfusion.

• Glycine participates in the transport of bile acids!

Glycine conjugation is an important physiological process where bile acids are conjugated to glycine, which allows the bile acids to pass through the cell membrane.

• Glycine is also important for the detoxification mechanism!

For example, delayed development of the enzyme glycine-N-acyltransferase in children can compromise the detoxification of various drugs and xenobiotics.

• Glycine is also an osmoprotectant against stress!

Stresses such as high temperature, desiccation and urea concentration environments. For example, accumulation of glycine betaine appears to be a mechanism by which Escherichia coli can adapt to external osmotic forces and grow in hypertonic urine. Such amino acids as glycine are believed to stabilize enzymes, nucleic acids, membrane-bound proteins and intracellular organelles.

Glycine: Essential metabolic player

A large number of biochemical metabolic reactions take place in the body in which glycine is an important participant. Some of these metabolic processes are:

• One-carbon metabolism – involves the transfer of active groups with one carbon.
• Glycine cleavage system – implies a complex containing four enzyme components, which performs glycine cleavage and thus its metabolism.
• Uteroplacental use – glycine is a conditionally essential amino acid in the newborn. The placenta consumes glutamine and glycine. In addition, serine from maternal plasma is used in the utero-placental tissue to produce glycine, some of which is delivered to the fetal circulation. In turn, the fetal liver is the main site for the decarboxylation of glycine and the synthesis of serine from glycine.
• Signal transmission in the nervous system – glycine in the spinal cord and brain stem acts as an inhibitory neurotransmitter. Glycine-mediated inhibitory neurotransmission is essential for startle responses, voluntary motor control, and sensory signal processing in the spinal cord. Glycine transporter inhibitors can be used in the treatment of muscle tone disorders, epilepsy, schizophrenia, pain and neurodegenerative disorders. It is recognized by a receptor located on the ion channel. Ion channels are protein pores within the cell membrane that transport ions that play a key role in maintaining cell integrity, which supports cell volume maintenance, signal transduction between cells, etc. In this context, mutations in the glycine receptor gene have been found to cause inherited motor disorders, and spinal shock flaccidity is associated with high local concentrations of glycine. 

• Interesting facts:

• The spider Araneus diadematus is able to produce silk with a range of mechanical properties through gland-specific gene expression that alters the proportion of glycine-rich domains.
• Collagen, which is present in all multicellular organisms, is the most abundant protein in mammals. It is rich in glycine molecules and it is now believed that mutations leading to the replacement of glycine with other amino acids can lead to serious functional defects. Some of these diseases are Ehlers-Danlos syndrome type IV, osteogenesis imperfecta and epidermolisis bullosa pruriginosa.
• Glycine is also of primary importance for the synthesis of macromolecules such as hemoglobin in the blood and myoglobin in the muscles.

Innovative Uses of Glycine: Advancing Applications

• The low molecular weight made glycine a suitable amino acid for addition to commercial nutrient solutions to increase their nitrogen content.
• In clinical use, parenteral intake of glycine as a dietary supplement is safe. Glycyl-glutamine dipeptide infusion is used in patients with polytrauma. Studies have also confirmed the safety of glycine in patients with schizophrenia and, in rehydration fluids, in children with diarrhea.⁸
• Different research projects have focused on the use of glycine as a supplement with other specific amino acids, such as glutamine.
• Radioactive glycine can be used to measure protein metabolism. It has been observed that glutamine exerts its anabolic effect by increasing protein synthesis, while the amount of glycine isonitrogen only decreases protein turnover. However, glycine can act as a regulator of glutamine metabolism within liver cells, hepatocytes.
• Since glycine is one of the amino acids in the blood that decreases in states of shock, the immunoregulatory role of glycine may be very important in further applications of glycine in the diet.

Based on various studies and applications, it is reasonable to assume that glycine would be useful in the treatment of many inflammatory-type diseases in humans. Obvious disease targets include sepsis and endotoxemia, which occur in many patients after abdominal surgery or trauma. It is also reasonable to think that glycine may be useful in many respiratory diseases such as asthma. Furthermore, the use of glycine in the prevention and/or treatment of certain types of cancer appears promising. All these considerations should stimulate further research into the clinical application of dietary glycine. Since glycine can be increased simply by dietary measures, the feasibility of therapeutic and preventive approaches for many diseases with this new immunonutrient is entirely promising.

References:

[1] A.A. Jackson, The glycine story, Eur. J. Clin. Nutr. 45 (1991) 59–65.

[2] M. Díaz-flores, M. Cruz, G. Duran-reyes, C. Munguia-miranda, H. Loza-rodríguez, E. Pulido-casas, N. Torres-ramírez, O. Gaja-rodriguez, J. Kumate, L.A. Baiza-gutman, D. Hernández-saavedra, With Metabolic Syndrome , Improving Their Systolic Blood Pressure, 860 (2013) 855–860.

[3] E. Meléndez-Hevia, P. de Paz-Lugo, G. Sánchez, Glycine can prevent and fight virus invasiveness by reinforcing the extracellular matrix, J. Funct. Foods. 76 (2021). https://doi.org/10.1016/j.jff.2020.104318.

[4] P.D. Godfrey, R.D. Brown, Shape of Glycine, J. Am. Chem. Soc. 117 (1995) 2019–2023. https://doi.org/10.1021/ja00112a015.

[5] M.C. Gannon, J.A. Nuttall, F.Q. Nuttall, The metabolic response to ingested glycine, Am. J. Clin. Nutr. 76 (2002) 1302–1307. https://doi.org/10.1093/ajcn/76.6.1302.

[6] C. Aragón, B. López-Corcuera, Structure, function and regulation of glycine neurotransporters, Eur. J. Pharmacol. 479 (2003) 249–262. https://doi.org/10.1016/j.ejphar.2003.08.074.

[7] R.Y. Gundersen, P. Vaagenes, T. Breivik, F. Fonnum, P.K. Opstad, Glycine – An important neurotransmitter and cytoprotective agent, Acta Anaesthesiol. Scand. 49 (2005) 1108–1116. https://doi.org/10.1111/j.1399-6576.2005.00786.x.

[8] J.C. Hall, Review: Glycine, J. Parenter. Enter. Nutr. 22 (1998) 393–398. https://doi.org/10.1177/0148607198022006393.

[9] M.D. Wheeler, K. Ikejema, N. Enomoto, R.F. Stacklewitz, V. Seabra, Z. Zhong, M. Yin, P. Schemmer, M.L. Rose, I. Rusyn, B. Bradford, R.G. Thurman, Glycine: A new anti-inflammatory immunonutrient, Cell. Mol. Life Sci. 56 (1999) 843–856. https://doi.org/10.1007/s000180050030.

[10] Glycine molecule amino acid functional group protein – PNG, (n.d.). https://favpng.com/png_view/molecule-glycine-molecule-amino-acid-functional-group-protein-png/8Nj8JgZV.

[11] Amino acid glycine the chemical molecular formula vector image on VectorStock, (n.d.). https://www.vectorstock.com/royalty-free-vector/amino-acid-glycine-the-chemical-molecular-formula-vector-36740213.