Glycine Amino Acids: Properties, Function, Benefits, and Sources
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What is glycine?
Glycine is the smallest of the amino acids and con-sists of a carbon molecule attached to an amino and a carboxyl group. This has made it a convenient amino acid to add to commercial solutions of nutrients to increase their nitrogen content. This use as a "stuffer" amino acid has extended into research projects evaluating supplementation with specific amino acids, such as glutamine, to ensure that the control solutions are isonitrogenous. It was recently proposed by Smith that a combination of non-essential amino acids should take the place of glycine as an improper "control" amino acid. There is growing evidence that glycine can protect cells from damage, which lends credence to this idea. Research assessing nutrient regimens for severely sick individuals will be greatly affected by this. It implies that control solutions containing a lot of glycine could introduce significant confounding effects.
Glycine structure
The amino acid glycine is the most basic one for making proteins. It is unique among amino acids in that it contains a hydrogen atom on its side chain, setting it apart from all others. Belonging to the serine family, it is an alpha-amino acid. Glyoxylate, glucose (via serine), betaine, and perhaps threonine are some of the sources of glycine that humans produce. It is also synthesized endogenously with l-carnitine. Regardless, investigations on various animal models have shown that glycine could be conditionally essential, meaning that an organism's metabolic demands cannot always be supplied by the quantity that the body synthesizes. In order to maintain a healthy glycine plasma concentration between 200 and 300 mol/L, it is essential to consume 1.5-3 g of glycine daily. Since glycine does not have a large side chain—which may change its physical properties by adding charge, hydrophobicity, or other structural constraints—its functions are related to its diminutive size and absence of such a chain. Because of these characteristics, glycine is able to serve as a biologic modifier in a number of contexts and play an essential function in the structure of specific proteins.
Chemical structure of glycine. (Quintanilla-Villanueva G E., et al., 2024)
Glycine pKa
Glycine can react with both acids and bases in water because it is amphoteric. It is simple to prepare the hydrochloride salt by adding HCl to a solution. The glycine hydrochloride salt, with a pKa of 2.3 after the first deprotonation and a pKa of 9.6 after the second deprotonation, is obtained by evaporating the solvent. With a pKa of 2.87, chloroacetic acid is more basic than glycine hydrochloride. Chloroacetic acid has a lower pKa than acetic acid (pKa = 4.75 ~ 2 units) because the negative charge in the conjugate base is stabilized by the adjacent electron withdrawing chlorine group. Keep in mind that pKa is measured on a logarithmic scale. The pKa drops even further to 2.3 in the conjugate base of glycine hydrochloride because the adjacent positive charge stabilizes the conjugate base's negative charge.
Assignment of cysteine and glycine pKa values. (Işık M., et al., 2018)
pKa and pKb values for glycine. (Sebastiani F., et al., 2021)
Glycine solubility
Glutamine dissolves readily in water and other aqueous solutions because of its high solubility. Under atmospheric pressure, utilizing a dynamic laser method, the solubility of α-glycine in water with various additions (sodium nitrate, ammonium nitrate, ammonium sulfate, and ammonium chloride) was evaluated at intervals of 10.00 K throughout the temperature range of (293.15-343.15) K. As the temperature and additive level were raised, the solubility was seen to rise. The exothermic mixing process of α-glycine was demonstrated by the estimated HE values in all the systems that were tested.
Different aqueous solutions were used to measure the solubilities of two glycine polymorphs, α-form and γ-form. By graphing the measured solubility data in water according to the van't Hoff equation, we were able to compute the enthalpy and entropy of dissolution for both forms. At the temperature range of 5 to 60 °C, the α-form is the metastable form, while the γ-form shows a lower solubility and higher energy of dissolution compared to the α-form. This suggests that the γ-form is the stable form. In both the methanol with water and PEG200 with water solvent mixes, the γ-form had lower solubilities than the α-form. Both forms become less soluble when methanol and PEG200 are added, which means that these substances can be employed as antisolvents to remove glycine from water and cause it to crystallize. We looked at the pH range of (0.35 to 13.7) to see how different values affected the γ-form's solubility in water at (20 and 25) °C. The solubility curve has a U-shape, with the isoelectric point (pH 5.9) being the point of minimum solubility.
Solubility data of glycine in water with different additives. (Sebastiani F., et al., 2021)
Glycine sources
Mammals, including humans, rats, and pigs, produce glycine, according to previous nutritional and isotopic investigations. These studies demonstrated, in particular, that (1) young animals could thrive without glycine in their food and (2) the body produced new, unlabeled glycine, which significantly diluted 15N-glycine in physiological fluids like plasma. Meanwhile, rat biochemical experiments demonstrated three pathways that might convert serine to glycine: (1) SHMT, which forms serine hydroxymethyltransferase; (2) sarcosine, which forms choline; and (3) threonine, which forms glycine via the threonine enzyme. Later research confirmed that pigs and other animals also had these three glycine production routes. According to recent research, animals can synthesize glycine using hydroxyproline and glyoxylate as substrates. As a result of reducing consumption of both nutritionally important and non-essential amino acids, the rate of whole-body glycine synthesis in young adult men who consume 44 kcal of energy and 1.5 g of protein per kg of body weight per day drops to 116 mg/kg of body weight/day. The rates of whole-body glycine synthesis in fed young rats are 1.99 g/kg BW/day, while in fed adult rats it is 1.29 g/kg BW/day. This lines up with the idea that rats have a faster metabolic rate than humans.
Synthesis of glycine from glucose and glutamate, serine, choline, and threonine in animals. (Wang W., et al., 2013)
What does glycine do?
Glycine has essential roles in the metabolism and nutrition of numerous mammals including humans. Glycine constitutes 11.5% of the overall amino acid content in the human body, and it accounts for 20% of the total amino acid nitrogen in body proteins. Typically, 80% of the total glycine in the human body, as well as in other animals, is utilized for protein synthesis. In collagen, glycine occupies every third position; glycine residues facilitate the formation of the collagen triple helix. Glycine contributes to the flexibility of active sites of enzymes. In the central nervous system, glycine serves a vital function as a neurotransmitter, regulating food intake, behavior, and overall body homeostasis. Glycine modulates immunological activity, superoxide generation, and cytokine synthesis by modifying intracellular Ca2+ concentrations. Glycine facilitates the conjugation of bile acids in humans and pigs, hence playing an essential role in the absorption and digestion of lipid-soluble vitamins and lipids. RNA, DNA, creatine, serine, and heme are synthesized through various mechanisms that employ glycine. Glycine plays a vital role in cytoprotection, immunological response, growth, development, metabolism, and the survival of humans and various other mammals.
Functions and metabolic fate of glycine. (Razak M A., et al., 2017)
Glycine amino acids at Creative Peptides
What is glycine used for?
(1) Reduce Hepatotoxicity
It has been found that glycine can enhance the functions of several enzymes, including g-glutamyltranspeptidase, alkaline phosphatases, asparatate transaminases, tissue fatty acid composition, and alanine transaminase. Therefore, taking glycine orally can help protect against alcohol-induced liver damage. Further, by keeping membranes intact, glycine can optimize or alter lipid levels in response to persistent alcohol feeding. Blood alcohol levels were found to be extremely low in rats that were given glycine supplements. As a great preventative measure to lower blood alcohol levels, glycine was reported by Iimuro et al. (2000). In rats subjected to continuous alcohol feeding, glycine modulates the individual composition of free fatty acids in the brain and liver, among its other effects, including a decrease in the buildup of free fatty acids. According to the data and research presented above, glycine is a powerful antioxidant that successfully combats ethanol-induced toxicity. In order to lessen the damage, glycine slows down the rate at which the stomach empties of ethanol. Animal studies have shown that glycine supplementation ameliorates alcohol-induced hyperlipidemia by lowering lipid levels. Oral administration of glycine inhibits the ability of acetaldehyde and other alcohol metabolic byproducts to induce changes in the carbohydrate moieties of glycoproteins, as demonstrated in the scientific literature. Furthermore, glycine has the ability to combat oxidative stress in hepatocytes, plasma, and erythrocyte membranes in both animals and humans that have experienced alcohol-induced liver damage. The in vivo study showed that glycine inhibits endothelial cell proliferation and angiogenesis, which in turn prevents hepatic cancer and some melanomas like B16. On top of all that, glycine suppresses Ca2+-dependent degradation by nonlysosomal proteases like calpains, which means it can prevent potentially fatal cell damage like hypoxia. In addition to curing stroke, schizophrenia, benign prostatic hyperplasia, and a few uncommon inherited metabolic illnesses, glycine supplementation has the potential to cure other conditions. The glycine diet can protect the kidneys from the adverse effects of certain medicines following an organ transplant. Reducing the terrible effects of alcohol is what glycine is all about. An ischemic stroke is the most typical indication for the topical application of glycine, however it can also heal various leg ulcers and sores. A protective effect against hepatotoxicity is exhibited by glycine. A human diet must contain 2 glycine grammes per day to meet the body's requirements. Healthy dietary options include things like meat, fish, dairy, and legumes. Rats with hemorrhagic shock have a reduced death rate and less organ damage when administered intravenously with glycine prior to resuscitation, according to the findings. An oral dose of glycine mitigates the endotoxic shock damage produced by D-galactosamine and cyclosporine A.
Glycine blocks tumor necrosis factor, inflammation, and macrophage activation. Additionally, glycine mitigates alcohol-induced liver damage, lipid peroxidation reperfusion injury, and glutathione shortage brought on by several hepatotoxins. Along with its essential part in processes like haem, purine, and gluconeogenesis, glycine also plays a role in chlorophyll synthesis and bile acid conjugation. Glycine and alanine have unique properties that work together to enhance alcohol metabolism. Neutrophils' superoxide ion levels are reduced by glycine via glycine gated chloride channels. The chloride channels in Kupffer cells are triggered by glycine, which causes the cell membrane to hyperpolarize and reduce intracellular Ca2+ concentrations; glycine also performs comparable tasks in neurons. Too much glycine in a supplement can be harmful to humans. The rapid metabolism of glycine in the digestive tract is the main shortcoming of taking the supplement orally. Glycine aids in the first-pass elimination of alcohol from the stomach, which in turn stops the alcohol from reaching the liver.
(2) Treatment of gastrointestinal disorders
According to Jacob's team, glycine prevents harm to the stomach during mesenteric ischemia by reducing cell death. In a way that is compatible with glycine absorption, Lee's team in 2002 showed that glycine protects against intestinal IR damage. Glycine is utilized as a substrate by many membrane transport mechanisms in the intestinal mucosa to enhance cellular absorption. The basolateral membrane of enterocytes contains the GLYT1 receptor, whose primary role is to bring glycine into the cells. Glycine primarily serves to meet the needs of the enterocyte within the cell. Howard's team in 2010 investigated the role of GLYT1 in glycine's cytoprotective effects against oxidative stress using cell lines from human intestinal epithelial cells. Glycine safeguards intracellular glutathione levels without affecting glycine absorption rate when administered prior to oxidative stress. The specific function of the GLYT1 receptor is critical for maintaining intracellular glutathione levels. Accumulation of glycine within cells is facilitated by the GLYT1 receptor.
Glycine prevents chemical models of colitis brought on by trinitrobenzene sulfonic acid or dextran sulfate sodium, according to Tsune's group. Glycine alleviated the skin irritation and damage that dextran sulfate sodium and trinitrobenzene sulfonic acid had on the epithelium. In contrast to glycine's anti-inflammatory effects on various molecular targets of other mucosal cell populations, Howard's team found that glycine's direct effects on intestinal epithelial cells could affect the overall inflammatory status of the intestine through a substantial change in redox status. Glycine has therapeutic and preventative uses; it was shown that taking an oral supplement of glycine for two days following the administration of 2,4,6-trinitrobenzene sulfonic acid [TNBS] significantly reduced inflammation. It is challenging to dissect the various mechanisms by which glycine reduces inflammation and injury because of its capacity to alter the various cell types. To further understand the cytoprotective and anti-inflammatory properties of glycine, additional research into the precise functions of glycine receptors on immune cells and epithelial cells is necessary. Supplemental glycine is highly effective in preventing a number of gastrointestinal problems.
(3) Prevent organ transplantation failure
The preservation of organs in cold ischemia for transplantation results in ischemia-reperfusion damage, a primary factor contributing to organ transplantation failure. The failure of organ transplantation can be mitigated with glycine treatment. Glycine therapy ameliorated cold and hypoxia ischemia damage in the kidneys of rabbits and dogs, enhancing graft function post-transplantation. Furthermore, kidneys immersed in glycine-based Carolina solution can be safeguarded from reperfusion and storage injuries, hence improving renal graft performance and prolonging survival following kidney transplantation. The application of glycine in organ transplantation is predominantly studied in liver transplantation. The use of glycine into the Carolina rinse solution and cold storage solution mitigates storage and reperfusion injuries while simultaneously improving graft function and health by reducing nonparenchymal cell damage in rat liver transplantation. Administering glycine intravenously to donor rats will significantly enhance the graft survival rate. Currently, non-heart-beating donors are increasingly recognized as a valuable source of transplantable organs due to the critical lack of donor organs for clinical use. Grafts from non-heart-beating donors get treatment with 25 mg/kg of glycine during normothermic recirculation to mitigate reperfusion injury to endothelial and parenchymal cells post-organ transplantation. Following human liver transplantation, glycine is administered intravenously to mitigate reperfusion injury. Prior to implantation, recipients receive 250 ml of 300 mM glycine for one hour, followed by a daily administration of 25 ml of glycine post-transplantation. The elevated transaminase levels are diminished to one-fourth, and bilirubin levels are also reduced. Glycine mitigates pathological alterations, including reduced villus height, venous congestion, and villus epithelial loss, decreases neutrophil infiltration, and improves oxygen delivery and blood circulation.
A significant factor contributing to reduced graft survival is rejection. Glycine possesses the capability to modulate the immune response and aids in mitigating transplant rejection. A dose-dependent reduction in antibody titer occurs in rabbits exposed to sheep erythrocyte antigen and typhoid H antigen when administered large doses of glycine ranging from 50 to 300 mg/kg. The dietary glycine, in conjunction with a low dose of cyclosporine A, promotes the survival rate of allografts in kidney transplantation from DA to Lewis rats and improves renal function compared to very low doses of cyclosporine A alone. No research evidence indicate that glycine alone enhances graft survival. Glycine serves as a protective agent for gel-entrapped hepatocytes in a bioartificial liver. 3 mM of glycine exhibits optimal protective capacity and can inhibit cell necrosis following anoxic exposure. The aforementioned data demonstrate that glycine possesses modest immunosuppressive effects.
(4) Glycine treatment for Hemorrhagic and Endotoxic Shock
Endotoxic and hemorrhagic shock frequently occur in critically unwell patients. Hypoxia, activation of inflammatory cells, coagulation disturbances, and the release of toxic mediators are primary factors contributing to multiple organ failure. The aforementioned events responsible for multiple organ failure can be substantially mitigated by glycine; thus, glycine can be effectively utilized in shock therapy. Glycine enhances survival and diminishes organ harm following resuscitation or hemorrhagic shock in a dose-dependent fashion. Another study shown that glycine significantly decreases transaminase release, mortality, and liver necrosis during hemorrhagic shock. The endotoxin therapy induces liver necrosis, pulmonary damage, elevated blood transaminase levels, and mortality, which can be ameliorated by short-term glycine administration. Continuous administration of glycine for four weeks reduces inflammation and increases survival following endotoxin exposure, although does not ameliorate liver damage. The observed effect following continuous glycine administration results from the downregulation of glycine-gated chloride channels on Kupffer cells, but not on neutrophils or alveolar macrophages. Glycine enhances survival rates by mitigating pulmonary inflammation. Glycine enhances liver function, ameliorates liver injury, and reduces mortality in experimental sepsis induced by cecal puncture and ligation. The scientific literature indicates that glycine is highly effective in safeguarding against septic, endotoxin, and hemorrhagic shock.
(5) Gastric ulcer treatment by glycine
Glycine diminishes acid secretions induced by pylorus ligation. Glycine also safeguards against induced stomach lesions in rats resulting from indomethacin, hypothermic-restraint stress, and necrotizing chemicals including 0.6 M hydrochloric acid, 0.2 M sodium hydroxide, and 80% ethanol. Glycine exhibits significant cytoprotective and antiulcer properties. Additionally, further research is crucial to elucidate the mechanisms of glycine's effects on gastrointestinal disorders and to determine its involvement in the treatment and prevention of gastric ulcer disease.
(6) Preventive property of glycine for arthritis
Glycine, an effective immunomodulator that mitigates inflammation, is examined in vivo for its effects on arthritis using the PG-PS model. PG-PS is a vital structural element of Gram-positive bacterial cell walls and induces rheumatoid-like arthritis in mice. In rats injected with PG-PS exhibiting infiltration of inflammatory cells, synovial hyperplasia, edema, and ankle swelling, glycine supplementation can mitigate the effects of the PG-PS model of arthritis.
(7) Cancer therapy
Polyunsaturated fatty acids and peroxisome proliferators are effective tumor promoters due to their capacity to enhance cell proliferation. Kupffer cells are excellent providers of mitogenic cytokines, including TNFα. Dietary glycine can inhibit cell proliferation induced by WY-14,643, a peroxisome proliferator, and maize oil. Glycine inhibits the generation of TNFα by Kupffer cells and the activation of nuclear factor κB. Glycine inhibits 65% of tumor growth in implanted B16 melanoma cells, suggesting its anticancer properties.
(8) Maintain vascular health
The presence of glycine gated chloride channels in rat platelets was shown by one of the researchers. Human platelets also show glycine gated chloride channel expression and glycine responsiveness, according to their research. Preadministration of 500 mg/kg of glycine could decrease myocardial ischemia reperfusion damage. After in vitro cardiomyocytes were exposed to ischemia for one hour and then reoxygenated, one of the researchers showed that 3 mM glycine supported an increased survival rate. The ex vivo model of myocardial ischemia reperfusion similarly showed protection from 3 mM glycine. In rats given sucrose, Sekhar et al. found that glycine reduced blood pressure.
(9) Amelioration of metabolic syndrome in obesity and diabetes
The rising rates of obesity in both children and adults make it one of the most pressing health issues of the modern era. Type II diabetes and an early mortality are both made more likely by this metabolic disease. Obesity characterized by an excess of belly fat is significantly more linked to problems with glucose and lipid metabolism than subcutaneous fat obesity, according to a number of cardiovascular research. Regional accumulation of body fats is also a major risk factor for cardiovascular illnesses. Glycine concentrations in plasma are lower in those with diabetes and obesity, which is an interesting finding. The potential of glycine supplementation as a new treatment for obesity and type II diabetes is becoming more apparent. In an animal model of intra-abdominal obesity, glycine supplementation reduces concentrations of free fatty acids and triglycerides, adipocyte size, and adiposity. In diabetic rats, type-2 diabetic patients, and type-1 diabetic rats, it inhibits nonenzymatic glycation of lens proteins and hemoglobin. First, glycine improves insulin sensitivity; second, it increases anti-oxidative and anti-inflammatory capacity; and third, it normalizes the secretion of triglyceride-rich very low-density lipoproteins from the liver by triggering neuronal transmission in the dorsal vagal complex through the N-methyl-d-aspartate receptor, which can lead to therapeutic benefits in obesity and type 2 diabetes.
(10) Animal growth and development
Birds, such as chickens, actively generate uric acid through a glycine-dependent route and are unable to synthesize adequate glycine to fulfill metabolic requirements. Consequently, glycine should be incorporated into meals to facilitate optimal growth and development of avian species. The optimal dietary glycine content for maximal growth and feed conversion efficiency in broilers aged 7 to 20 days is approximately 1.0%. Conversely, glycine was formerly regarded as a nutritionally nonessential amino acid for mammals, encompassing humans and pigs. Wu has posited that glycine is a nutritionally essential amino acid for sow-reared piglets and postweaning pigs, as their dietary intake of glycine is inadequate for tissue protein synthesis under conventional feeding conditions. Powell's team discovered that the glycine synthesis rate in 20–50 kg pigs on a low-protein diet (a 5% reduction in crude protein content) may be insufficient for optimal growth performance. The authors additionally indicated that dietary supplementation with 0.52% glycine can enhance average daily growth and feed efficiency in developing pigs to values comparable to those observed in pigs consuming a standard protein diet. Dietary supplementation with 1.7% glycine did not enhance growth performance, likely due to its detrimental impact on the transport and use of neutral amino acids in the body.
Physiological functions of glycine in animals and humans. (Wang W., et al., 2013)
Glycine's main positive impacts on cardiovascular health. (Quintanilla-Villanueva G E., et al., 2024)
References
- Quintanilla-Villanueva G E., et al., The Role of Amino Acid Glycine on Cardiovascular Health and Its Beneficial Effects: A Narrative Review, Journal of Vascular Diseases, 2024, 3(2): 201-211.
- Işık M., et al., pKa measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments, Journal of computer-aided molecular design, 2018, 32: 1117-1138.
- Sebastiani F., et al., Probing local electrostatics of glycine in aqueous solution by THz spectroscopy, Angewandte Chemie International Edition, 2021, 60(7): 3768-3772.
- Yang X., et al., Solubility of Form α and Form γ of Glycine in Aqueous Solutions, Journal of Chemical & Engineering Data, 2008, 53(5): 1133-1137.
- Wang W., et al., Glycine metabolism in animals and humans: implications for nutrition and health, Amino acids, 2013, 45: 463-477.
- Razak M A., et al., Multifarious beneficial effect of nonessential amino acid, glycine: a review, Oxidative medicine and cellular longevity, 2017, 2017(1): 1716701.
- Wheeler M D., et al., Glycine: a new anti-inflammatory immunonutrient, Cellular and Molecular Life Sciences CMLS, 1999, 56: 843-856.
- Li P., et al., Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth, Amino acids, 2018, 50: 29-38.
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