Glycine: The Smallest Anti-Inflammatory Micronutrient
Karla Aidee Aguayo-Cerón 1, Fausto Sánchez-Muñoz 2 , Rocío Alejandra Gutierrez-Rojas 3, Lourdes Nallely Acevedo-Villavicencio 1, Aurora Vanessa Flores-Zarate 1, Fengyang Huang
REVIEW article Front. Aging, 13 May 2025
Volume 6 – 2025 | https://doi.org/10.3389/fragi.2025.1452917
Abstract:
Glycine is a non-essential amino acid with many functions and effects. Glycine can bind to specific receptors and transporters that are expressed in many types of cells throughout an organism to exert its effects. There have been many studies focused on the anti-inflammatory effects of glycine, including its abilities to decrease pro-inflammatory cytokines and the concentration of free fatty acids, to improve the insulin response, and to mediate other changes. However, the mechanism through which glycine acts is not clear. In this review, we emphasize that glycine exerts its anti-inflammatory effects throughout the modulation of the expression of nuclear factor kappa B (NF-B) in many cells. Although glycine is a non-essential amino acid, we highlight how dietary glycine supplementation is important in avoiding the development of chronic inflammation.
1. Introduction
Glycine, also known as amino acetic acid, is an important component of many proteins and plays a crucial role in the synthesis of many biomolecules, including creatine and
purine nucleotides [1]. Glycine was first isolated in 1820 from the acid hydrolysis of gelatine. Its name is derived from the Greek word glykys, meaning sweet, and it is the
smallest amino acid (with a molecular weight of 75.067 g/mol). It is located in both the hydrophilic and hydrophobic parts of the polypeptide chain [2,3]. It is abundant in plasma
and represents 11.5% of the total amino acids and 20% of the nitrogen in body proteins and accounts for 80% of protein [4,5]. The necessary dietary intake of glycine is ~1.5–3 g/day [6]
given that in young men, glycine flux is 34–35 mg/kg/h on average in the fed state; during the post-absorptive state, the glycine flux is decreased by half (around 18 mg/kg/h) [7,8].
Around 35% of glycine in the body comes from endogenous synthesis [9], and the average rate of whole-body de novo glycine synthesis is estimated at 12–15 mg/kg/h, contributing
to 81% of the systemic flux [2,7,10]. The physiological glycine plasma concentration ranges from 200 to 300 mol/L [11].
Glycine is synthesized endogenously by the body from serine, choline, threonine, and glyoxylate [12,13]; hence, it has been classified as an unessential amino acid for mammals [4]
that has many activities in different systems (Figure 1). Glycine acts as a neurotransmitter and modulates neuronal activity [14]; its main activity is related to the inhibition of different
brain regions. For example, in the central nervous system (CNS), glycine binds to chloridesensitive ion channels to inhibit postsynaptic neurons [15]. It plays an important role
in the mechanism of pain transmission: pharmacological treatment or genetic deletion that inhibits glycinergic signaling is sufficient to evoke pain hypersensitivity in living organisms [16]. Glycine has also been associated with the control of motor functions due to its ability to ameliorate motor deficiencies after surgery [17]. Glycine also plays an important role in the regulation of gene expression [18], protein configuration and activity, and several other biological functions [19]. There are other beneficial activities in which glycine is involved: as antacid, modulator of growing throughout the regulation of growth hormone (GH) synthesis; improves muscle tone, collagen synthesis, tissue restore (scar formation) and delaying muscular degeneration [20], in addition, it has been reported that glycine also protects the intestine against the harmful effects of radiotherapy in cancer treatment [21].
Figure 1. Glycine effects. Glycine is an aminoacid synthetized endogenous and there has been describe many activities in which it participates that include a variety of systems. Glycine has a protective effect in lung, brain, stomach, and intestine; participates in metabolic process; modulate process of the immune system such as tissue regeneration, decrease necrosis, sepsis protection; and finally, glycine is considerate as a genic expression modulator
Glycine plays a role in diabetes. It is a secretagogue of glucagon-like peptide-1 (GLP-1) [22], insulin, and glucagon [23] because it has been shown that the effect of ingested glycine on the postprandial glucose concentration facilitates the secretion of insulin by other amino acids [24].
Decreased glycine receptor (GlyR) expression in cells from people with type 2 diabetes mellitus (T2DM) is associated with a disruption of glycine-induced insulin secretion [25]. Clinical studies have shown that higher circulating glycine concentrations help lower the risk of developing T2DM [26].
The objective of this review is to integrate information from basic and clinical studies regarding the role of glycine as a therapeutic agent to regulate the low-grade inflammation associated with disease. We also integrated the possible mechanism throughout glycine could act as a ligand and it has an effect by activation of different pathways related to inflammation process in a variety of cells that belong to different systems
The role of glycine as a therapeutic agent to regulate the low-grade inflammation associated with disease. We also integrated the possible mechanism throughout glycine could act as a ligand and it has an effect by activation of different pathways related to inflammation process in a variety of cells that belong to different systems.
2. Glycine Targets
According to the International Union of Basic and Clinical Pharmacology (IUPHAR), glycine has the following natural/endogenous targets: GlyRs (with 1, 2, 3, 4, and subunits), a co-agonist of ionotropic glutamate receptors (GluN1, GluN2A, GluN2B, GluN2C, and GluN2D), G protein-coupled receptor family C group 6 (GPRC6), and transporters, which move this compound across lipid membranes. The transporters include glycine transporter type 1 and 2 (GlyT1 and GlyT2, respectively), proton-coupled amino acid transporter 1, vesicular inhibitory amino acid transporter, proton-coupled amino acid transporter 2, neutral amino acid transport (B0AT1, B0AT2, B0AT3, and NTT4), sodiumcoupled neutral amino acid transporter 1, sodium-coupled neutral amino acid transporter 2, sodium-coupled neutral amino acid transporter 4, and sodium-coupled neutral amino acid transporter 5 [27–30].
3. Receptors
3.1. GlyRs
GlyRs are ligand-activated pentameric ion channels that belong to the Cys-loop family of transmitter-activated ion channels (zinc-activated channels). This family also include -aminobutyric acid receptor type A (GABAA); nicotinic acetylcholine receptors; N-methyl-D-aspartate (NMDA) receptors, which are ionotropic glutamate receptors (iGluRs); and serotonin receptor 5-hydroxytryptamine type 3 (5HT3R) [15,31,32]. GlyRs are abundantly expressed throughout the CNS: there are postsynaptic, presynaptic [15], and extrasynaptic GlyRs [33]. There are four known GlyR subunits ( 1– 4) and a single subunit in vertebrates [34]. Normally, the subunit is part of a heteromultimeric complex with GlyR subunits [35].
GlyRs are expressed as homopentamers of five subunits or as heteropentamers of three and two subunits or two subunits and three subunits. The receptor is an intrinsic anion channel [34,36–38]. As mentioned above, there are four subunits, namely, 1, 2, 3, and 4, and a single gene coding for the subunit [39,40]. The four subunits generally share >90% amino acid sequence homology with each other, but their genes are expressed in specific zones and are developmentally regulated. The 2 subunit is highly expressed in all layers of the cerebral cortex, brain stem, thalamus, spinal cord, hippocampus, diencephalon, and cerebellum during embryonic development [41,42]. There is a change from 2 homomeric GlyRs to 1 heteromeric GlyRs during development [15]. In neonatal period, levels of 1 and 3 expression increase. 1 is prominently expressed in the hypothalamus, colliculi, the spinal cord, and brain stem cerebellar deep nuclei [43,44]. 3 has a relatively lower level of expression than 1 at all developmental stages [45,46]. 4 is an embryonic GlyR subunit isoform [40] but is presumed to be a pseudogene in humans due to a premature stop codon upstream of the final TM4 domain. The subunit gene is transcribed at all developmental stages and is widely and abundantly distributed in the
spinal cord and brain [47,48]. Its distribution is broader than that of 1. The subunit is indispensable for synaptic clustering [49].
When glycine binds to GlyRs, the channel opens (it is formed by the domine 2 of each subunit of the GlyR) and generates a short-term flux of negative ions into the cell. In this way, the intracellular chlorine concentration increases temporarily, leading to hyperpolarization of the membrane, which prevents the cell from being easily excited (Figure 2). The net effect is inhibitory [50,51]. GlyRs are involved in several processes, including the central regulation of orexigenic signals in obesity [52].
Figure 2. Glycine targets and pathways. According to the International Union of Basic & Clinical Pharmacology (IUPHAR) glycine has different targets such as Natural/Endogenous Targets: glycine receptor (consisting of glycine receptor α1, α2, α3, α4 and β subunits), ionotropic glutamate receptors co-agonist (GluN1, GluN2A, GluN2B, GluN2C and GluN2D) and GPRC6 Receptor. Transporters moving this compound across a lipid membrGluN2C and GluN2D) and GPRC6 Receptor. Transporters moving this compound across a lipid membrane with proton-coupled amino acid transporter 1, vesicular inhibitory amino acid transporter, Proton-coupled Amino acid Transporter 2, GlyT1, GlyT2, B0AT1, B0AT2, B0AT3, NTT4, sodium-coupled neutral amino acid transporter 1, sodiumcoupled neutral amino acid transporter 2, sodium-coupled neutral amino acid transporter 4, Sodium- coupled neutral amino acid transporter 5 [27–30]. These may be the targets involved in theneutral amino acid transporter 5 [27–30]. These may be the targets involved in the signaling by which glycine exerts its effect on the different cell lines of living organisms