GLYCINE
Glycine is an amino acid that plays a crucial role in a wide range of physiological processes. It is involved in the synthesis of proteins, neurotransmitters, and other important molecules in the body. Additionally, recent research has revealed that glycine supplementation can play both stimulatory and depressant roles in the brain. Glycine supplementation can improve sleep quality.
In this article, we will explore the benefits of glycine supplementation on these areas of health in greater detail. We will examine the scientific research that has been conducted on glycine and its effects on various physiological processes. By the end of this article, you will have a deeper understanding of the potential health benefits of glycine and how it may be used as a supplement to improve overall health and well-being.
Table of Contents
- History
- Sources
- Properties
- Biological Activity
- Deficiency
- Metabolism
- Glycinergic Neurotransmission
- Glutaminergic Neurotransmission
- Memory & Learning
- Schizophrenia & Obsession
- Sleep & Sedation
- Cardiovascular Disease Risk
- Insulin Sensitivity
- Blood Glucose & Insulin
- Diabetes
- Interactions With Hormones
- Nutrient Interactions
- Safety & Toxicity
- Side Effects & Adverse Events
- Summary
History
The discovery of glycine, which is abbreviated as Gly, dates back to 1820 when a French chemist named Henri Braconnot used acid hydrolysis of gelatin to isolate this amino acid. With only a single hydrogen atom as its side chain, glycine is the simplest amino acid known to exist in nature. Interestingly, glycine has a level of sweetness similar to glucose, which is why it was named after the Greek word “glykys,” meaning sweet.
Sources
Collagen, the most abundant protein in the human body, contains a significant amount of glycine. In fact, glycine constitutes one-third of the amino acids in collagen, and it appears in the repeated form of tripeptides, namely glycine-proline-Y and glycine-X-hydroxyproline, where X and Y can represent any amino acid. [1]
While collagenous proteins are considered the most abundant source of glycine in our diets, protein from various dietary sources also provides varying amounts of this amino acid. According to the USDA Food Composition Database, cooked meats and seafood typically contain 1-2 grams of glycine per 100 grams of food, while eggs provide 0.4 grams of glycine per 100 grams of whole egg, and milk offers 0.08 grams of glycine per 100 grams of milk.
Aside from dietary sources, glycine can also be synthesized by the body itself. The primary pathway for glycine synthesis involves the conversion of serine through an enzyme called glycine hydroxymethyltransferase (GHMT), which produces approximately 2.5 grams of glycine per day. Additionally, glycine can be synthesized in smaller amounts (around 0.5 grams per day) through choline (via sarcosine), the degradation of threonine, the synthesis of carnitine, and the transamination of glyoxylate.
Properties
Glycine is a crystalline solid that is colorless, odorless, and possesses a sweet taste. Its molecular weight is 75.067 g/mol. As with all amino acids, glycine features a central carbon atom that is bonded to an amino group, a carboxylic acid group, and a unique side chain. In the case of glycine, its side chain comprises a single hydrogen atom, which makes glycine the most basic and smallest amino acid found in nature. Being a neutral and nonpolar amino acid, glycine does not carry an electrical charge and is generally unreactive towards water.
Biological Activity
Glycine performs various critical functions in the body, primarily through its structural and regulatory activities. As an amino acid, glycine plays a crucial role in protein synthesis, particularly in the synthesis of collagen. A glycine molecule must represent every third amino acid in collagen for stability, and mutations that result in substitutions of glycine results in a variety of connective tissue disorders collectively known as brittle bone disease.
Glycine also plays a vital role in the structure and function of enzymes by providing flexibility in their active sites, allowing them to change their conformation as necessary to bind with substrates. [1]
Glycine is a precursor for the synthesis of several biologically important compounds, including porphyrins and heme, creatine (glycine + arginine + methionine), glutathione (glycine + cysteine + glutamate) and purines. Moreover, glycine also serves a crucial role in the digestion and absorption of lipids. It gets conjugated with bile acids (along with taurine) before excretion into the biliary system.
Additionally, glycine functions as a crucial signaling molecule throughout the body by acting as both an inhibitory and excitatory neurotransmitter in the brain and spinal cord. It plays a pivotal role in various physiological processes, including reflex coordination, processing of sensory signals, and the perception of pain.
The inhibitory effects of glycine are attributed to its direct binding to glycine-specific receptors, whereas the excitatory effects are mediated by glutamate and the N-methyl-D-aspartate (NMDA) receptor. [1]
Beyond the nervous system, glycine also plays a critical role in immunomodulation and inflammation. It achieves this by binding chloride channels in the cell membranes of leukocytes and macrophages, which in turn suppresses calcium influx.
Main Takeaway: Glycine is a vital amino acid that serves multiple crucial roles in the body. It is essential for protein synthesis, particularly collagen synthesis, and is involved in the biosynthesis of heme, creatine, glutathione, and purines. Furthermore, glycine acts as a neurotransmitter in the nervous system, where it can function as both an inhibitory and excitatory molecule. In addition, glycine plays a role in the immune system as a signaling molecule and is necessary for some enzyme functions. Lastly, glycine is involved in lipid digestion and absorption by being conjugated with bile acids before being excreted into the biliary system.
Deficiency
In humans, glycine is a conditionally essential amino acid because the body cannot produce enough of it to meet metabolic needs. According to research, an average sedentary adult human (70 kg; 30-50 years) requires approximately 15 grams of glycine per day to produce collagen (12 g/d), non-collagen proteins (1 g/d), porphyrins (240 mg/d), purines (206 mg/d), creatine (420 mg/d), glutathione (567 mg/d), and bile salts (60 mg/d). However, glycine synthesis is limited to around 2.5 grams per day, which means humans need to consume about 12 grams of dietary glycine to meet daily metabolic needs.
According to nitrogen balance studies, glycine’s essentiality is further supported. In a controlled feeding study conducted on healthy young men, it was found that decreasing total protein intake from 1.5 g/kg (3.8 g glycine) to 0.6 g/kg (1.5 g glycine) did not affect the rates of glycine synthesis, but providing these protein amounts exclusively from essential amino acids led to a significant reduction in de novo glycine synthesis. The reduction was 37% for 1.5 g/kg and 66% for 0.6 g/kg.
Reducing total protein intake from 1.5 g/kg (3.8 g glycine) to 0.4 g/kg (1.0 g glycine) led to a significant reduction in de novo glycine synthesis of about 40% in young men and 33% in elderly men.
These studies suggest that the amino acid composition of the diet influences glycine metabolism, especially at low total protein intakes. If glycine were truly nonessential, then its synthesis in the body should not depend on dietary intake.
The imbalance between glycine synthesis and requirements in humans has been explained from an evolutionary perspective. Collagen is the most prevalent protein in the animal kingdom and was initially present in small animals that required low quantities relative to their size, so glycine synthesis was sufficient for their survival. However, larger animals did not appear to develop new metabolic pathways and therefore inherited a regulatory system that was not well-suited to their significantly increased collagen demands.
This evolutionary explanation requires that the glycine biosynthesis constraint applies to any large animal. Glycine is supplemented in the diets of livestock to maximize growth, collagen production, skeletal muscle development, nitrogen retention, mucin production, immune function, antioxidant capacity.
The essential role of glycine in collagen production raises the possibility that the development of skeletal and joint diseases in aging animals and humans could be an example of Bruce Ames’ Triage Theory. This theory proposes that when nutrient availability is limited, short-term survival takes precedence over long-term health.
Intake of 10 grams of glycine per day in the diet has the potential to increase serum concentrations, which is linked to a significant rise of 200% in the rates of type-II collagen synthesis when compared to the current levels of glycine in the body.
A glycine shortage also affects glutathione status. Glutathione is created from the amino acids: glutamate, cysteine, and glycine. Glutamate and cysteine combine to form gamma-glutamylcysteine, which then combines with glycine to form glutathione. People with genetic defects in this latter step show increased levels of urinary 5-oxoproline (pyroglutamic acid). Increased urinary 5-oxoproline concentrations have also been found after depleting the body’s glycine pool with benzoic acid and after feeding healthy adults a glycine-free diet. Supplementating with glycine has been shown to reduce urinary 5-oxoproline concentrations and increase glutathione status. A chronic glycine shortage could, therefore, have long-term implications for the body’s exposure to oxidative stress.
Urinary 5-oxoproline levels serve as a way to identify populations that do not obtain enough glycine to support glutathione synthesis. Vegetarians have significantly higher levels of 5-oxoproline than omnivores, and higher 5-oxoproline levels significantly correlated with lower dietary protein intake.
Preterm infants have higher urinary levels of 5-oxoproline than full-term infants and nitrogen balance studies have suggested that glycine supplementation may be necessary to assure a satisfactory rate of lean tissue growth in preterm infants.
Main Takeaway: Glycine is an amino acid that is considered conditionally essential for humans. To meet metabolic demands, an estimated 12 grams of glycine per day is required through the diet, as humans are not able to synthesize enough glycine to satisfy their needs. Although glycine insufficiency is not life-threatening, chronic shortage may have negative impacts on collagen turnover and glutathione status, leading to increased oxidative stress and a higher risk of skeletal and joint diseases.
Delivery
Peak serum glycine concentrations are typically observed 30-60 minutes following glycine ingestion. [1] When consumed as a peptide, glycine elicits a larger and faster peak compared to when it is ingested as a free amino acid. Individuals with systemic infections may experience enhanced glycine absorption, while those with type II diabetes may experience reduced absorption. Glucose has been found to inhibit glycine absorption, but its practical significance is considered to be low. [1]
Metabolism
Glycine is degraded by via the glycine cleavage enzyme system, converted into serine, or used for biosynthesis of proteins, porphyrins, purines, creatine, glutathione, and bile salts. It also plays a central role in protein synthesis, especially collagen, where it represents every third amino acid in the protein’s primary structure.
Glycinergic Neurotransmission
There are a few transporters that draw glycine into cells, and they appear to have a regulatory role in controlling levels of synaptic glycine.
Glycine itself is a neurotransmitter with its own signalling system (similar to GABA or Agmatine). This system is inhibitory and works in conjunction with the GABAergic system. However, studies have shown a developmental shift favoring glycinergic inhibition in the auditory brainstem [1] and hypoglossal nucleus. Glycinergic neurotransmission has also been found to play a role in the thalamus, cerebellum and hippocampus. [1]
Glutaminergic Neurotransmission
Glycine plays a part in glutaminergic neurotransmission by binding to NMDA receptors, which are a type of glutamate receptor. These receptors are usually made up of tetramers, consisting of two glycine-binding units (known as GluN1 subunits) and glutamate-binding units (GluN2). [1, 2, 3] The GluN1 subunit has eight different splice variants.
Both glycine (D-serine may be used as well) and glutamate are necessary to induce signaling on the GluN1 receptors, making these glutamate receptors known as “glycine-dependent.” Glycine is considered a “coagonist” in this context. [1]
100μM or higher (30μM ineffective) appears to potentiate NDMA signalling and appears to be concentration-dependently increased up until 1,000μM,which is thought to be due to how glycine binding sites are unsaturated due to efficient buffering systems.
Memory & Learning
Functional glycine receptors have been observed in the hippocampus, indicating the presence of a glycinergic system with inhibitory effects on neuronal excitation. [1] These receptors are mainly located extrasynaptically but are also colocalized with synapsin.
Upon neuronal activation, hippocampal cells are capable of releasing glycine. [1, 2] Immunohistology studies have shown that glycine is mainly stored presynaptically alongside glutamate,and most glycine clusters observed are positioned towards NMDA glutaminergic receptors.
Main Takeaway: Glycine is implicated in hippocampal signaling, and evidence suggests that both the glycinergic and glutaminergic systems can play a role in this process.
Schizophrenia & Obsession
800mg/kg of glycine daily for six weeks in persons with schizophrenia on stable antipsychotic therapy noted that supplementation was associated with a 23+/-8% reduction in negative symptoms and a lesser but also therapeutic effect on cognitive and positive symptoms.
There is a documented case study of a person with both OCD and body dysmorphic disorder who experienced a notable decrease in symptoms over five years while taking a daily dose of 800mg/kg glycine. This is the same dose used in trials for schizophrenia. The authors of the study suggested that the individual’s symptoms may have been related to inadequate NDMA receptor signalling, and improvements were observed within 34 days of starting the treatment.
Sleep & Sedation
When 3g of glycine was given to female participants one hour before sleep, it was observed that glycine supplementation resulted in reduced fatigue upon waking up and an improvement in self-reported sleep quality when compared to a placebo group.
A study conducted on healthy individuals who reported poor sleep quality tested the effects of 3g of glycine. The participants underwent an electroencephalography (EEG) via polysomnography, and the results showed that glycine improved the subjective quality of sleep by reducing the time it took to fall asleep and the time it took to enter slow wave sleep, as well as improved cognitive day-time performance associated with better self-reported sleep. However, glycine did not affect rapid eye movement (REM) sleep or overall sleep architecture.
A study conducted on individuals with mild sleep problems found that taking 3g of glycine one hour before bedtime reduced fatigue the following day. However, this effect was no longer significant after three days. The study also found that glycine consistently improved performance on psychomotor vigilance tasks.
Main Takeaway: Supplementing with low doses of glycine seems to improve the feeling of a restful night’s sleep, decrease the time taken to fall asleep, and enhance performance the following day. However, the positive effect on the feeling of restful sleep lasts only for a day, while the improvement in performance persists.
Cardiovascular Disease Risk
Plasma glycine concentrations have been significantly associated with an 11% reduced risk of suffering a heart attack in a cohort of 4109 adults from Norway over a 7.4-year follow-up.
Insulin Sensitivity
Research has found a correlation between low serum glycine levels and insulin resistance.
However, studies using Mendelian randomization and controlled trials suggest that the low levels of glycine may be a result of insulin resistance, rather than a causal factor in its development. [1, 2, 3]
Blood Glucose & Insulin
Taking small to moderate doses of glycine (3-5 grams) along with meals has been found to reduce the body’s glucose response after eating. [1, 2, 3] This effect may be attributed to an increase in insulin response via GLP-1. Glycine has also been reported to significantly increase the insulin response to hyperglycemia during a hyperglycemic clamp when 5 grams is consumed 30 minutes beforehand.
Diabetes
Interactions With Hormones
A single 22.5g bolus (the administration of a discrete amount of medication, drug, or other compound within a specific time, generally 1–30 minutes, to raise its concentration in blood to an effective level) of glycine has been reported to significantly increase growth hormone concentrations for up to 180 minutes after ingestion in healthy men and women.
Nutrient Interactions
Glycine is sometimes bound to minerals such as zinc or magnesium as a ‘diglycinate’ chelation, which enables the minerals to be absorbed via peptide transporters in an intact form [1] which tends to lead to enhanced absorption relative to the free form of the mineral in the upper intestine. Diglycine tends to be absorbed rather than hydrolyzed which makes it an efficient carrier.
Main Takeaway: Diglycinate, which consists of two glycine molecules in a dipeptide form, is commonly used to increase the absorption of mineral supplements. This is because minerals bound to a dipeptide can be absorbed through a different set of transporters than free minerals.
Safety & Toxicity
Side Effects & Adverse Events
Glycine supplementation was well tolerated without major adverse effects in a study involving 10 obese adults supplementing with 5 grams of glycine at each of three meals (15 g/d).
Glycine is well tolerated and does not cause daytime sleepiness when supplemented with meals, but 9 grams on an empty stomach has been noted to cause mild abdominal discomfort.
Summary
Glycine is a vital amino acid that serves multiple crucial roles in the body. It is essential for protein synthesis, particularly collagen synthesis, and is involved in the biosynthesis of heme, creatine, glutathione, and purines. Furthermore, glycine acts as a neurotransmitter in the nervous system, where it can function as both an inhibitory and excitatory molecule. In addition, glycine plays a role in the immune system as a signaling molecule and is necessary for some enzyme functions. Lastly, glycine is involved in lipid digestion and absorption by being conjugated with bile acids before being excreted into the biliary system.
Glycine is an amino acid that is considered conditionally essential for humans. To meet metabolic demands, an estimated 12 grams of glycine per day is required through the diet, as humans are not able to synthesize enough glycine to satisfy their needs. Although glycine insufficiency is not life-threatening, chronic shortage may have negative impacts on collagen turnover and glutathione status, leading to increased oxidative stress and a higher risk of skeletal and joint diseases.
Glycine is well tolerated and does not cause daytime sleepiness when supplemented with meals, but 9 grams on an empty stomach has been noted to cause mild abdominal discomfort.
Glycine is implicated in hippocampal signaling, and evidence suggests that both the glycinergic and glutaminergic systems can play a role in this process.
A daily dosage of 800mg/kg of glycine appears to induce a reduction in negative symptoms and a lesser but also therapeutic effect on cognitive and positive symptoms in people with schizophrenia and OCD.
Supplementing with low doses of glycine seems to improve the feeling of a restful night’s sleep, decrease the time taken to fall asleep, and enhance performance the following day. However, the positive effect on the feeling of restful sleep lasts only for a day, while the improvement in performance persists.
Plasma glycine concentrations have been significantly associated with an 11% reduced risk of suffering a heart attack.
There appears to be a correlation between low serum glycine levels and insulin resistance, however low levels of glycine may be a result of insulin resistance, rather than a causal factor in its development.
Taking small to moderate doses of glycine (3-5 grams) along with meals has been found to reduce the body’s glucose response after eating. Glycine has also been reported to significantly increase the insulin response to hyperglycemia during a hyperglycemic clamp when 5 grams is consumed 30 minutes beforehand.
Supplementation with 5 grams of glycine per meal (15 g/d) for three months has been reported to benefit glycemic control in patients with type II diabetes.
Diglycinate, which consists of two glycine molecules in a dipeptide form, is commonly used to increase the absorption of mineral supplements. This is because minerals bound to a dipeptide can be absorbed through a different set of transporters than free minerals.
