Glycine

Glycine, chemically represented as NH2CH2COOH, is the simplest amino acid and plays pivotal roles in various biochemical processes within living organisms. Glycine is precursor for a variety of important metabolites such as glutathione, porphyrins, purines, haem, and creatine. Glycine acts as neurotransmitter in central nervous system and it has many roles such as antioxidant, anti-inflammatory, cryoprotective, and immunomodulatory in peripheral and nervous tissues [1]. 

Glycine's discovery dates back to the early 19th century when Henri Braconnot first isolated it from gelatin broth in1820, christening it "glycocolle" due to its sweet taste. However, its structure was elucidated later by Ernst Schulze and Pierre-Eugène-Marcellin Berthelot in 1858. Structurally, glycine consists of a single hydrogen atom as its side chain, making it the simplest amino acid. Its chemical structure comprises an amino group, a carboxylic acid group, and a hydrogen atom attached to a central carbon atom.

Metabolic Pathways:

Glycine is a non-essential amino acid, meaning that it can be synthesized by the body from other amino acids. Glycine is found in all living organisms, and it plays a variety of important roles in the body.

1. Glycine Synthesis:

Glycine can be synthesized from threonine (via the threonine dehydrogenase pathway), choline (through the formation of sarcosine), serine (via serine hydroxymethyltransferase), hydroxyproline and glyoxylate [1]. The conversion of serine to glycine is central to the a series of interconnected metabolic pathways. The enzyme Serine Hydroxymethyltransferase (SHMT) facilitates the reversible transfer of a methyl group from serine to tetrahydrofolate (THF), yielding glycine and 5,10-methylenetetrahydrofolate (5,10-CH2-THF), an integral reaction within the one-carbon metabolism pathway [2,3].

2. Glycine Degradation

Glycine can be catabolized in the body through the glycine cleavage system (GCS) pathway [4]. The reaction is catalyzed by the glycine cleavage system (GCS), consists of four protein components: P-protein (glycine decarboxylase), H-protein (glycine cleavage system H protein), T-protein (aminomethyltransferase), and L-protein (dihydrolipoyl dehydrogenase). The P-protein catalyzes the cleavage of glycine into carbon dioxide, ammonia, and a one-carbon unit which is transferred to THF by the T-protein. Glycine Dehydrogenase (GLDC), also known as P-protein within the GCS, catalyzes the oxidative cleavage of glycine to produce CO2, NH3, and a methylene-tetrahydrofolate (THF) intermediate.Aminomethyltransferase (AMT), also known as the T-protein within the GCS, it transfers the one-carbon unit from glycine to THF to generate 5,10-methylenetetrahydrofolate (5,10-CH2-THF).

3. Interconversions

 Glycine can undergo interconversion with various metabolites. For instance, it can be oxidatively deaminated by the enzyme glycine dehydrogenase to produce glyoxylate, which can then participate in various metabolic pathways, including the glyoxylate cycle. Alternatively, glycine can be methylated by the enzyme glycine-N-methyltransferase to form sarcosine, which is involved in the metabolism of methionine and creatine.

4. Interconnected Pathways

The metabolism of glycine is closely interconnected with several other metabolic pathways. For example, it is linked to the one-carbon metabolism, where 5,10-MTHF generated during glycine catabolism serves as a crucial intermediate for the synthesis of purines, thymidine, and methionine [5]. Additionally, the metabolism of glycine intersects with the pathways involved in amino acid metabolism, energy production, and redox balance, highlighting its central role in cellular metabolism.

The Role of Glycine in Diseases

Glycine, an amino acid, serves numerous crucial functions within the body, including protein synthesis, neurotransmission, and biosynthesis of important molecules like heme, creatine, and glutathione. Recent research has shed light on its role in various diseases, underscoring its significance beyond its traditional metabolic functions. Here's an overview:

1. Glycine in Neurological Disorders

Schizophrenia: Glycine acts as a co-agonist at the N-methyl-D-aspartate (NMDA) receptor. Research suggests that dysfunction in the glycine/NMDA receptor system may contribute to schizophrenia. Glycine modulators are being explored as potential adjunctive treatments for this disorder [5,6].

Stroke: Glycine receptors play a role in ischemic brain injury. Recent studies indicate that targeting glycine receptors could offer neuroprotection against stroke-induced damage [7,8]. glycine improved cell apoptosis, inflammatory response and glucose metabolism disorder of ischemic stroke through miR-19a-3p/AMPK/GSK-3β/HO-1 pathway. [9].

Alzheimer's disease (AD): Glycine deficiency disrupts glutamate-glycine NMDA receptor signaling, impairing cognitive function and promoting neurodegeneration. Studies suggest potential in supplementing glycine to alleviate cognitive decline in AD patients [10].

Parkinson's disease (PD): Glycine depletion weakens the inhibitory action of glycine neurons, leading to excitotoxicity and neuronal death. Enhancing glycine availability through glycine transporter type 1 (GlyT1) agonists shows promise in mitigating PD symptoms [11].

2. Glycine in Metabolic Disorders

Diabetes: Glycine has been investigated for its potential role in mitigating insulin resistance and oxidative stress associated with diabetes. Studies suggest that glycine supplementation may improve insulin sensitivity and reduce inflammation in diabetic individuals [12].

Obesity: Research indicates that glycine supplementation could help regulate energy balance and mitigate obesity-related metabolic dysfunction by influencing adipose tissue function and insulin signaling pathways [13].

3. Glycine in Inflammation

Glycine has significant anti-inflammatory effects, acting as a regulator and mediator in the body's immune response. It inhibits the production of pro-inflammatory cytokines like IL-6, TNF-alpha, and IL-1β, dampens the activation of immune cells such as macrophages and neutrophils, and promotes the differentiation of regulatory T cells. Additionally, glycine inhibits the activation of NF-κB, a key transcription factor in inflammation, and stimulates the production of anti-inflammatory cytokines like IL-10. By modulating these pathways, glycine helps protect tissues from damage caused by inflammation, making it a potential therapeutic agent for inflammatory conditions and diseases. [14,15].

4. Glycine in Cancers

Glycine exerts multifaceted roles in cancer biology, influencing various aspects of tumor development, progression, and response to therapy [2,3,16,17]. It is essential for cancer cell proliferation and survival, contributing to nucleotide and protein synthesis, as well as metabolic reprogramming. Additionally, glycine metabolism plays a role in epigenetic regulation through its involvement in S-adenosylmethionine synthesis, impacting gene expression and chromatin remodeling. Moreover, glycine can modulate immune responses within the tumor microenvironment and influence the behavior of stromal cells, promoting tumor angiogenesis and metastasis. Dysregulated glycine metabolism in cancer cells may contribute to immune evasion and tumor immune escape. Targeting glycine metabolism has emerged as a potential therapeutic strategy for cancer treatment, with inhibitors of glycine uptake or metabolism showing promise in sensitizing tumors to chemotherapy or immunotherapy. Understanding the complex roles of glycine in cancer biology may lead to the development of novel therapeutic approaches for cancer management.

5. Glycine in Cardiovascular Diseases

Glycine plays crucial roles in cardiovascular health and disease by regulating nitric oxide production, exerting anti-inflammatory and antioxidant effects, modulating lipid metabolism, and influencing platelet function [18-20]. It enhances nitric oxide production, which contributes to improved endothelial function and vasodilation. Additionally, glycine mitigates inflammation by reducing pro-inflammatory cytokines and inhibiting NF-κB activation, while its antioxidant properties counteract oxidative stress, protecting against cardiovascular damage. Glycine also influences lipid metabolism, leading to improved lipid profiles and reduced risk of atherosclerosis. Furthermore, it modulates platelet function, inhibiting platelet activation and aggregation to prevent thrombotic events. Overall, glycine exhibits cardioprotective effects, making it a potential therapeutic target for cardiovascular diseases.

References:

1. Razak, M. A., Begum, P. S., Viswanath, B., & Rajagopal, S. (2017). Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review. Oxidative medicine and cellular longevity, 2017, 1716701. https://doi.org/10.1155/2017/1716701

2. Amelio, I., Cutruzzolá, F., Antonov, A., Agostini, M., & Melino, G. (2014). Serine and glycine metabolism in cancer. Trends in biochemical sciences, 39(4), 191–198. https://doi.org/10.1016/j.tibs.2014.02.004

3. Pan, S., Fan, M., Liu, Z., Li, X., & Wang, H. (2021). Serine, glycine and one‑carbon metabolism in cancer (Review). International journal of oncology, 58(2), 158–170. https://doi.org/10.3892/ijo.2020.5158

4. Kikuchi, G., Motokawa, Y., Yoshida, T., & Hiraga, K. (2008). Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proceedings of the Japan Academy. Series B, Physical and biological sciences, 84(7), 246–263. https://doi.org/10.2183/pjab.84.246

5. de Bartolomeis, A., Manchia, M., Marmo, F., Vellucci, L., Iasevoli, F., & Barone, A. (2020). Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia. Frontiers in psychiatry, 11, 369. https://doi.org/10.3389/fpsyt.2020.00369

6. Correll C. U. (2020). Current Treatment Options and Emerging Agents for Schizophrenia. The Journal of clinical psychiatry, 81(3), MS19053BR3C. https://doi.org/10.4088/JCP.MS19053BR3C

7. Cappelli, J., Khacho, P., Wang, B., Sokolovski, A., Bakkar, W., Raymond, S., Ahlskog, N., Pitney, J., Wu, J., Chudalayandi, P., Wong, A. Y. C., & Bergeron, R. (2021). Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke. iScience, 25(1), 103539. https://doi.org/10.1016/j.isci.2021.103539

8. Fan, D., Krishnamurthi, R., Harris, P., Barber, P. A., & Guan, J. (2019). Plasma cyclic glycine proline/IGF-1 ratio predicts clinical outcome and recovery in stroke patients. Annals of clinical and translational neurology, 6(4), 669–677. https://doi.org/10.1002/acn3.743

9. Chen, Z. J., Zhao, X. S., Fan, T. P., Qi, H. X., & Li, D. (2020). Glycine Improves Ischemic Stroke Through miR-19a-3p/AMPK/GSK-3β/HO-1 Pathway. Drug design, development and therapy, 14, 2021–2031. https://doi.org/10.2147/DDDT.S248104

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11. Sur, C., & Kinney, G. G. (2007). Glycine transporter 1 inhibitors and modulation of NMDA receptor-mediated excitatory neurotransmission. Current drug targets, 8(5), 643–649. https://doi.org/10.2174/138945007780618535

12. 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

13. Alves, A., Lamarche, F., Lefebvre, R., Drevet Mulard, E., Bassot, A., Chanon, S., Loizon, E., Pinteur, C., Bloise, A. M. N. L. G., Godet, M., Rautureau, G. J. P., Panthu, B., & Morio, B. (2022). Glycine Supplementation in Obesity Worsens Glucose Intolerance through Enhanced Liver Gluconeogenesis. Nutrients, 15(1), 96. https://doi.org/10.3390/nu15010096

14. Morozova, M. V., Borisova, M. A., Snytnikova, O. A., Achasova, K. M., Litvinova, E. A., Tsentalovich, Y. P., & Kozhevnikova, E. N. (2022). Colitis-associated intestinal microbiota regulates brain glycine and host behavior in mice. Scientific reports, 12(1), 16345. https://doi.org/10.1038/s41598-022-19219-z

15. Aguayo-Cerón, K. A., Sánchez-Muñoz, F., Gutierrez-Rojas, R. A., Acevedo-Villavicencio, L. N., Flores-Zarate, A. V., Huang, F., Giacoman-Martinez, A., Villafaña, S., & Romero-Nava, R. (2023). Glycine: The Smallest Anti-Inflammatory Micronutrient. International journal of molecular sciences, 24(14), 11236. https://doi.org/10.3390/ijms241411236

16. Jain, M., Nilsson, R., Sharma, S., Madhusudhan, N., Kitami, T., Souza, A. L., Kafri, R., Kirschner, M. W., Clish, C. B., & Mootha, V. K. (2012). Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science (New York, N.Y.), 336(6084), 1040–1044. https://doi.org/10.1126/science.1218595

17. Li, A. M., & Ye, J. (2020). Reprogramming of serine, glycine and one-carbon metabolism in cancer. Biochimica et biophysica acta. Molecular basis of disease, 1866(10), 165841. https://doi.org/10.1016/j.bbadis.2020.165841

18. Rom, O., Villacorta, L., Zhang, J., Chen, Y. E., & Aviram, M. (2018). Emerging therapeutic potential of glycine in cardiometabolic diseases: dual benefits in lipid and glucose metabolism. Current opinion in lipidology, 29(5), 428–432. https://doi.org/10.1097/MOL.0000000000000543

19. Millar, C. L., Anto, L., Garcia, C., Kim, M. B., Jain, A., Provatas, A. A., Clark, R. B., Lee, J. Y., Nichols, F. C., & Blesso, C. N. (2022). Gut microbiome-derived glycine lipids are diet-dependent modulators of hepatic injury and atherosclerosis. Journal of lipid research, 63(4), 100192. https://doi.org/10.1016/j.jlr.2022.100192

20. Biswas, S., Hilser, J. R., Woodward, N. C., Wang, Z., Gukasyan, J., Nemet, I., Schwartzman, W. S., Huang, P., Han, Y., Fouladian, Z., Charugundla, S., Spencer, N. J., Pan, C., Tang, W. H. W., Lusis, A. J., Hazen, S. L., Hartiala, J. A., & Allayee, H. (2023). Effect of Genetic and Dietary Perturbation of Glycine Metabolism on Atherosclerosis in Humans and Mice. medRxiv : the preprint server for health sciences, 2023.12.08.23299748. https://doi.org/10.1101/2023.12.08.23299748