Glycine is the simplest non-essential amino acid. Its molecular formula is C₂H₅NO₂ . It consists of an amino group (-NH₂), a carboxyl group (-COOH) and a hydrogen atom. Due to its unique structure, glycine is polar and hydrophilic, and as an amphoteric molecule, it can express both acidity and basicity. Glycine has many important biological functions in organisms. It is not only a constituent unit of protein synthesis, but also involved in key processes such as neurotransmitter synthesis, antioxidant defense (such as glutathione synthesis), and one-carbon unit metabolism. In addition, glycine occupies a core position in the metabolic network of animals, plants and microorganisms, and is an important node connecting multiple metabolic pathways. In this article, we will review the biosynthesis, catabolic, regulatory mechanisms and its relationship with diseases, in order to provide a reference for in-depth research on glycine metabolism.
Summary of Glycine
Glycine (chemical formula C₂H₅NO₂) is the simplest of the amino acid family and the smallest non-essential amino acid in the human body. Its structure consists of an amino group (-NH₂), a carboxyl group (-COOH) and a hydrogen atom, and has no side chain groups, so it has unique flexibility and functional diversity in protein synthesis.
Structural characteristics
The molecular formula of glycine is C2H5NO2 and the molecular weight is 75.06 g/mol. In its structure, amino and carboxyl groups are connected through a carbon atom, which is also connected to two hydrogen atoms. Due to the lack of side chains, glycine can exist in multiple three-dimensional conformations, which allows it to enter areas of the protein structure that other amino acids cannot, such as tight helical structures.
Figure 1. The Structure of Glycine. (Rousseaux, 2008)
Glycine exhibits amphoteric properties in aqueous solutions, that is, it is positively charged at pH values below 6.0 and negatively charged at pH values above 7.0. Its isoelectric point (pI) is 5.98, which means that at this pH, the total charge of glycine is zero.
Physicochemical properties
Glycine is easily soluble in water, but difficult to dissolve in organic solvents such as ethanol and ether. Its melting point is 223℃ and boiling point is 240℃. It has high solubility and thermal stability. In addition, glycine can form different crystal forms at different pH values, such as β-glycine and γ-glycine, which give glycine unique physical and chemical properties.
Service
Glycine synthesis in animals and microorganisms
Conversion from serine
In many microbial and animal cells, glycine is mainly converted from L-serine by the Serine Hydroxymethyltransferase (SHMT). The specific process of this reaction is: L-serine reacts with tetrahydrofolate to produce glycine, 5,10-methylene tetrahydrofolate and water. The SHMT enzyme contains the cofactor pyridoxal-5'-phosphate, which removes a carbon atom from the backbone of L-serine.
Reverse synthesis from glycine cleavage metabolic pathway
The Glycine Cleavage System (GCS) is usually involved in the catabolic metabolism of glycine, but in some cases, glycine can also be synthesized through reverse reactions. GCS consists of multiple enzymes that break down glycine into carbon dioxide, ammonia and methyltetrahydrofolate. Under certain conditions, this process can be reversed to synthesize glycine.
Figure 2.Glycine synthesis and cleavage metabolic pathway.
Produced from choline metabolism
Choline metabolism is also an important pathway for glycine synthesis. Choline is first oxidized to betaine, which then goes through a series of metabolic reactions and can finally produce glycine. This process involves the participation of multiple enzymes, including choline oxidase and betaine dehydrogenase.
Other secondary synthetic pathways
In addition to the main pathways mentioned above, there are also secondary pathways that can synthesize glycine. For example, in some microorganisms, glycine can be produced through the conversion of other amino acids or through specific metabolic by-passes.
Glycine synthesis in plants
The synthesis pathways of glycine in plants mainly include the following:
Through the photorespiratory pathway
In plants, photorespiration is an important metabolic process that is closely related to the synthesis of glycine. During photorespiration, glycolate oxidase in chloroplasts oxidizes glycolic acid to glyoxylic acid, which then generates glycine under the action of glyoxylic acid reductase. Glycine is further converted to serine by serine hydroxymethyltransferase (SHMT), completing the cyclic conversion between glycine and serine
One-carbon metabolism in chloroplasts to glycine synthesis
One-carbon metabolism mediated by tetrahydrofolate (THF) in chloroplasts plays a key role in glycine synthesis. Carbon produced by photosynthesis is converted to 3-phosphoglycerate (3-PGA) through the Calvin-Benson cycle, which can then be further converted to serine. Serine, as a precursor for glycine synthesis, forms glycine through the action of SHMT. In addition, methionine synthase in chloroplasts is also involved in this process, transferring methyl groups from 5-methyltetrahydrofolate to homocysteine to produce methionine, which is an important intermediate in glycine synthesis.
Regulation of Exogenous Nitrogen on Glycine Synthesis
Exogenous nitrogen sources such as nitrate and ammonium nitrogen play an important role in regulating glycine synthesis in plants. After nitrate is absorbed by plants, it is reduced to nitrite under the action of nitrate reductase, and then the nitrite is further reduced to ammonium nitrogen under the action of nitrite reductase. Ammonium nitrogen can be directly absorbed and utilized by plants and participates in the synthesis of amino acids, including the synthesis of glycine. In addition, the supply of external nitrogen sources will also affect the activity of one-carbon metabolism in plants, which in turn affects the synthesis of glycine.
Metabolic pathways of glycine
Glycine is an important non-essential amino acid in life. Its metabolic pathways are extensive and complex, involving multiple key biological processes. The following describes the metabolic pathway and function of glycine in detail from multiple aspects:
Glycine cleavage metabolism (GCS)
The glycine cleavage system (GCS) is an important metabolic pathway in mitochondria, which is mainly responsible for converting glycine into 5-10 carbon compounds (such as 5-10 methyltetrahydrofolate and carbon dioxide) and provides a key intermediate for one-carbon metabolism. GCS consists of multiple enzymes, including glycine decarboxylase (GLDC), accessory protein H, and methyltransferase (MAT). Among them, GLDC catalyzes the decarboxylation reaction of glycine, releasing carbon dioxide and producing 5-10 methyltetrahydrofolic acid.
The role of glycine in the one-carbon metabolic cycle
Glycine participates in the one-carbon metabolic cycle, especially the folic acid cycle, through GCS. In the folic acid cycle, 5-10 methyltetrahydrofolic acid acts as a methyl donor and participates in the synthesis of purine and pyrimidine nucleotides. In addition, GCS is also closely related to the metabolism of serine. Serine produces glyceraldehyde 3-phosphate through the action of dehydrogenase, which further enters the glycolenogenesis or TCA cycle.
Links to DNA, RNA, protein and lipid biosynthesis
Glycine is a precursor in the synthesis of a variety of biomolecules:
DNA and RNA synthesis: Glycine provides methylation units through the one-carbon metabolic pathway and is involved in the synthesis of purine and pyrimidine nucleotides.
Protein synthesis: Glycine is the basic building block of proteins and can serve as the second residue of the β-turn and is crucial for the formation of protein structure.
Lipid synthesis: Glycine is involved in the synthesis of bile acids and serves as a precursor of phospholipids and cholesterol.
The role of glycine in energy metabolism
Glycine plays an important role in energy metabolism:
Glycogenesis: Glycine can be converted into glucose through the glycogenesis pathway to replenish blood sugar levels.
TCA cycle supplements: Glycine can serve as a precursor of acetyl-CoA and succinyl-CoA and participate in the tricarboxylic acid cycle.
Oxidative phosphorylation: Glycine metabolism in mitochondria produces ATP through GCS, which supports the cell's energy needs.
Glycine and mitochondrial function and oxidative phosphorylation
The glycine cleavage system (GCS) is an important metabolic pathway in mitochondria. Its product, 5-10-methyltetrahydrofolic acid, is a key intermediate in the mitochondrial folic acid cycle, supporting nucleotide biosynthesis and methylation reactions. In addition, the activity of GCS is closely related to mitochondrial function, and its abnormality may lead to metabolic diseases.
As a multifunctional amino acid, glycine has a wide range of metabolic pathways and functions in organisms. Its cleavage system (GCS) plays a key role in energy metabolism, one-carbon metabolism, and nucleotide synthesis; at the same time, it is also an important precursor of biological molecules such as proteins, lipids, purines, and porphyrins. Therefore, in-depth research on the metabolic pathways of glycine is of great significance for understanding its role in health and disease.
Efficacy and metabolic characteristics of glycine in plants
The efficacy and metabolic characteristics of glycine in plants involve many aspects, including photorespiration, nitrogen metabolism, stress resistance applications, and its function as a signaling molecule in plant antioxidant and stress responses.
Role of glycine in plant photorespiration (C3 plants)
Photorespiration is an important process in carbon and nitrogen metabolism in C3 plants, and inhibitory intermediates generated through Rubisco catalyzed oxidation reactions are recycled back to the C3 pathway. Glycine plays a key role in photorespiration. It participates in the production of serine through glutamate transaminases (GGATs), thereby promoting the normal progress of photorespiration. Studies have shown that the accumulation of glycine during photorespiration can maintain the operation of the C3 pathway and prevent the destruction of the photosynthetic apparatus (Kaachra, A., et. al, 2018). In addition, increasing the photorespiration rate helps reduce the accumulation of intermediate metabolites, thereby improving photosynthetic efficiency.
Complementary effects of nitrogen metabolism
Glutamine is an important molecule in nitrogen assimilation in plants. It can be converted into glutamic acid during nitrogen metabolism and then produced other amino acids (including glycine) through the action of transaminases. Glycine can be converted to serine by serine hydroxymethyltransferase (SHMT) and further enters the glutamate metabolic pathway.
Effect of glycine on plant stress resistance
Glycine plays an important role in plant stress resistance. It can enhance plant stress resistance through a variety of mechanisms, such as improving photosynthesis efficiency, reducing oxidative stress, and inhibiting heavy metal absorption. Under abiotic stresses (such as drought and salt stress), glycine can protect plant cells by regulating plant hormone signaling pathways or enhancing antioxidant enzyme activity. In addition, glycine is also used as a target molecule for genetic engineering to improve plants 'adaptability to environmental pressures.
Antioxidant and stress response
Glycine functions as a signaling molecule in plant antioxidant and stress responses. It protects cells from oxidative damage by regulating reactive oxygen species (ROS) levels in plants. Under drought and salt stress conditions, glycine can reduce stress by promoting the activity of antioxidant enzymes such as glutathione peroxidase.
Glycine in different animal tissues
liver
Glycine has important metabolic functions in the liver. It participates in one-carbon metabolism and is converted to oxaloacetate or formic acid through the glycine cleavage system (GCS), while simultaneously releasing ammonia and carbon dioxide. In addition, glycine also participates in the synthesis of bile acids, combines with cholic acid to form glycerol cholate, which is excreted from the body with bile.
kidney
In the kidney, glycine is mainly involved in the reabsorption of amino acids. It enters tubular epithelial cells through specific transporters such as the SCL6 family and the SCL38 family and is reabsorbed back into the blood in the kidney. In addition, glycine also participates in the urea cycle, helping to eliminate excess ammonia in the body and maintain acid-base balance.
Muscle
Glycine is an important precursor for creatine synthesis in muscle tissue. Through the action of transaminases, glycine combines with arginine to produce creatine, which provides high-energy phosphate bonds to muscles, thereby supporting muscle activity. In addition, glycine can also provide energy to muscles by being converted to pyruvate or glucose.
Brain tissue
In brain tissue, glycine is an important inhibitory neurotransmitter that regulates the excitability of neurons. By binding to specific receptors, it inhibits the transmission of neural signals, thereby maintaining the steady state of the nervous system. In addition, glycine is also involved in regulating the balance of other neurotransmitters in the brain, such as dopamine and gamma-aminobutyric acid.
Figure 3. A model of dose-dependent bidirectional modifications of NMDA responses by glycine. (Zhang, X., et. al, 2014)
Analytical and detection methods for glycine metabolism
Analytical and detection methods for glycine metabolism cover a variety of technical means, including traditional amino acid detection methods, mass spectrometry technology, stable isotope tracing technology, etc.
Traditional amino acid detection methods
Traditional amino acid detection methods mainly include colorimetric method and high performance liquid chromatography (HPLC). Colorimetry is a quantitative analysis method that generates colored compounds based on specific chemical reactions and is suitable for rapid detection of the total amount of amino acids in samples. HPLC separates amino acids through a high performance liquid chromatography column and combines it with a detector for quantitative analysis. It has high sensitivity and selectivity.
Application of mass spectrometry in the study of glycine metabolism
LC-MS is one of the most commonly used analytical techniques in amino acid metabolism research. It combines the separation capabilities of liquid chromatography and the detection capabilities of mass spectrometry, and can simultaneously determine multiple amino acids and their metabolites, with high sensitivity and high selectivity. LC-MS is particularly suitable for analyzing highly polar amino acids and their derivatives without requiring complex derivatization.
Targeted metabolomics detects target metabolites in advance and is suitable for the study of specific metabolic pathways. Non-targeted metabolomics provides a comprehensive analysis of all metabolites and can reveal changes in unknown metabolites.
Stable Isotope Tracing Technology (SIRM)
Stable isotope tracing technology traces its metabolic path in organisms by introducing stable isotope labeled glycine. This approach can provide detailed information about metabolic pathways and help validate metabolic models.
Glycine metabolism and health and disease
Glycine is a non-essential amino acid that is widely involved in various metabolic processes and physiological functions of the human body. Its role in health and disease involves many aspects such as anti-oxidation, anti-inflammation, immune regulation and metabolic diseases.
Glycine and metabolic diseases
Diabetes and insulin sensitivity
Glycine has potential therapeutic effects on diabetes and its complications. Studies have shown that glycine improves insulin sensitivity, lowers blood sugar levels, and reduces insulin resistance. For example, in patients with type 2 diabetes, oral glycine significantly reduces glycosylated hemoglobin (HbA1c) levels (Cruz, M., et.al,2008)。
non-alcoholic fatty liver disease
Glycine also plays an important role in the prevention and treatment of NAFLD. Studies have found that glycine can reduce lipid accumulation in the liver and improve liver function. In addition, glycine supplementation can also promote lipid absorption and metabolism by regulating the binding of bile acids.
Obesity and metabolic syndrome
Glycine helps control weight and improve symptoms of metabolic syndrome by regulating energy metabolism and the breakdown of fatty acids. For example, it can reduce the size and number of fat cells and improve blood pressure and lipid levels.
Glycine and nervous system diseases
Schizophrenia: Research suggests that glycine may play a protective role in people with schizophrenia. It improves patients 'cognitive function and emotional state by regulating the balance of neurotransmitters.
Parkinson's disease: Glycine, as a neurotransmitter, has potential in the treatment of Parkinson's disease. It relieves symptoms and improves patients 'quality of life
Genetic diseases related to abnormal glycine metabolism
non-ketotic hyperglycinemia
Non-ketotic hyperglycinemia is a rare genetic disease characterized by abnormally elevated levels of glycine in the blood. This disease may be related to a disorder in the liver or kidney metabolism of glycine.
Genetic metabolic disease
Abnormal glycine levels may be associated with a variety of inherited metabolic diseases. For example, in some patients, gene mutations cause reduced enzyme activity, which affects the synthesis or utilization of glycine.
As a multifunctional amino acid, glycine plays an important role in maintaining human health and preventing disease. It functions through multiple mechanisms such as anti-oxidation, anti-inflammation, immune regulation and metabolic regulation. However, abnormal glycine metabolism may also lead to the occurrence and development of a variety of diseases, such as diabetes, obesity, non-alcoholic fatty liver disease, and nervous system diseases. Future research should further explore the specific mechanism of action of glycine in different diseases and develop diagnostic methods based on metabolomics and mass spectrometry to better utilize its potential therapeutic value.
References
- Rousseaux, Colin. (2008). A Review of Glutamate Receptors I: Current Understanding of Their Biology. Journal of Toxicologic Pathology. 21. 25-51. https://doi.org/10.1293/tox.21.25
- Kaachra, A., Vats, S. K., & Kumar, S. (2018). Heterologous Expression of Key C and N Metabolic Enzymes Improves Re-assimilation of Photorespired CO2 and NH3, and Growth. Plant physiology, 177(4), 1396–1409. https://doi.org/10.1104/pp.18.00379
- Zhang, X. Y., Ji, F., Wang, N., Chen, L. L., Tian, T., & Lu, W. (2014). Glycine induces bidirectional modifications in N-methyl-D-aspartate receptor-mediated synaptic responses in hippocampal CA1 neurons. The Journal of biological chemistry, 289(45), 31200–31211. https://doi.org/10.1074/jbc.M114.570630
- Cruz, M., Maldonado-Bernal, C., Mondragón-Gonzalez, R.,et.al. (2008). Glycine treatment decreases proinflammatory cytokines and increases interferon-gamma in patients with type 2 diabetes. Journal of endocrinological investigation, 31(8), 694–699. https://doi.org/10.1007/BF03346417
