Glycine

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File:Glycine-spin.gif

L-Glycine ball and stick model spinning

Glycine (symbol Gly or G;<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Template:IPAc-en)<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (GGU, GGC, GGA, GGG).<ref name=":3">Template:Cite journal</ref> Glycine disrupts the formation of alpha-helices in secondary protein structure. Its small side chain causes it to favor random coils instead.<ref name="pmid9649402">Template:Cite journal</ref> Glycine is also an inhibitory neurotransmitter<ref>Template:Cite journal</ref> – interference with its release within the spinal cord (such as during a Clostridium tetani infection) can cause spastic paralysis due to uninhibited muscle contraction.<ref>Template:Cite book</ref>

It is the only achiral proteinogenic amino acid.<ref>Template:Cite journal</ref> It can fit into both hydrophilic and hydrophobic environments, due to its minimal side chain of only one hydrogen atom.<ref>Template:Cite journal</ref>

History and etymology

Glycine was discovered in 1820 by French chemist Henri Braconnot when he hydrolyzed gelatin by boiling it with sulfuric acid.<ref>Template:Cite book</ref> He originally called it "sugar of gelatin",<ref>Template:Cite journal </ref><ref>Template:Cite book</ref> but French chemist Jean-Baptiste Boussingault showed in 1838 that it contained nitrogen.<ref>Template:Cite journal</ref> In 1847 American scientist Eben Norton Horsford, then a student of the German chemist Justus von Liebig, proposed the name "glycocoll";<ref>Template:Cite journal</ref><ref>Template:Cite book</ref> however, the Swedish chemist Berzelius suggested the simpler current name a year later.<ref>Template:Cite book From p. 654: "Er hat dem Leimzucker als Basis den Namen Glycocoll gegeben. ... Glycin genannt werden, und diesen Namen werde ich anwenden." (He [i.e., the American scientist Eben Norton Horsford, then a student of the German chemist Justus von Liebig] gave the name "glycocoll" to Leimzucker [sugar of gelatine], a base. This name is not euphonious and has besides the flaw that it clashes with the names of the rest of the bases. It is compounded from γλυχυς (sweet) and χολλα (animal glue). Since this organic base is the only [one] which tastes sweet, then it can much more briefly be named "glycine", and I will use this name.)</ref><ref>Template:Cite book</ref> The name comes from the Greek word γλυκύς "sweet tasting"<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> (which is also related to the prefixes glyco- and gluco-, as in glycoprotein and glucose). In 1858, the French chemist Auguste Cahours determined that glycine was an amine of acetic acid.<ref>Template:Cite journal</ref>

Production

Although glycine can be isolated from hydrolyzed proteins, this route is not used for industrial production, as it can be manufactured more conveniently by chemical synthesis.<ref>Template:Cite book</ref> The two main processes are amination of chloroacetic acid with ammonia, giving glycine and hydrochloric acid,<ref>Template:OrgSynth</ref> and the Strecker amino acid synthesis,<ref>Template:Cite book</ref> which is the main synthetic method in the United States and Japan.<ref name="usitc.gov">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> About 15 thousand tonnes are produced annually in this way.<ref name="Ull">Template:Cite book</ref>

Glycine is also co-generated as an impurity in the synthesis of EDTA, arising from reactions of the ammonia co-product.<ref name="Ullmann/Roger">Template:Ullmann</ref>

Chemical reactions

Its acid–base properties are most important. In aqueous solution, glycine is amphoteric: below pH = 2.4, it converts to the ammonium cation called glycinium. Above about pH 9.6, it converts to glycinate.

File:Glycine-protonation-states-2D-skeletal.png

Glycine functions as a bidentate ligand for many metal ions, forming amino acid complexes.<ref>Template:Cite journal</ref> A typical complex is Cu(glycinate)₂, i.e. Cu(H₂NCH₂CO₂)₂, which exists both in cis and trans isomers.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

With acid chlorides, glycine converts to the amidocarboxylic acid, such as hippuric acid<ref>Template:Cite journal</ref> and acetylglycine.<ref>Template:Cite journal</ref> With nitrous acid, one obtains glycolic acid (van Slyke determination). With methyl iodide, the amine becomes quaternized to give trimethylglycine, a natural product:

Template:Chem + 3 CH₃I → Template:Chem + 3 HI

Glycine condenses with itself to give peptides, beginning with the formation of glycylglycine:<ref>Template:Cite journal</ref>

2 Template:Chem → Template:Chem + H₂O

Pyrolysis of glycine or glycylglycine gives 2,5-diketopiperazine, the cyclic diamide.<ref>Template:Cite journal</ref>

Glycine forms esters with alcohols. They are often isolated as their hydrochloride, such as glycine methyl ester hydrochloride. Otherwise, the free ester tends to convert to diketopiperazine.

As a bifunctional molecule, glycine reacts with many reagents. These can be classified into N-centered and carboxylate-center reactions.

Metabolism

Biosynthesis

Glycine is not essential to the human diet, as it is biosynthesized in the body from the amino acid serine, which is in turn derived from 3-phosphoglycerate. In most organisms, the enzyme serine hydroxymethyltransferase catalyses this transformation via the cofactor pyridoxal phosphate:<ref name="Lehninger" />

serine + tetrahydrofolate → glycine + N⁵,N¹⁰-methylene tetrahydrofolate + H₂O

In E. coli, antibiotics that target folate depletes the supply of active tetrahydrofolates, halting glycine biosynthesis as a consequence.<ref>Template:Cite journal</ref>

In the liver of vertebrates, glycine synthesis is catalyzed by glycine synthase (also called glycine cleavage enzyme). This conversion is readily reversible:<ref name="Lehninger" />

CO₂ + NHTemplate:Su + N⁵,N¹⁰-methylene tetrahydrofolate + NADH + H⁺ ⇌ Glycine + tetrahydrofolate + NAD⁺

In addition to being synthesized from serine, glycine can also be derived from threonine, choline or hydroxyproline via inter-organ metabolism of the liver and kidneys.<ref>Template:Cite journal</ref>

Degradation

Glycine is degraded via three pathways. The predominant pathway in animals and plants is the reverse of the glycine synthase pathway mentioned above. In this context, the enzyme system involved is usually called the glycine cleavage system:<ref name="Lehninger" />

Glycine + tetrahydrofolate + NAD⁺ ⇌ CO₂ + NHTemplate:Su + N⁵,N¹⁰-methylene tetrahydrofolate + NADH + H⁺

In the second pathway, glycine is degraded in two steps. The first step is the reverse of glycine biosynthesis from serine with serine hydroxymethyl transferase. Serine is then converted to pyruvate by serine dehydratase.<ref name="Lehninger" />

In the third pathway of its degradation, glycine is converted to glyoxylate by D-amino acid oxidase. Glyoxylate is then oxidized by hepatic lactate dehydrogenase to oxalate in an NAD⁺-dependent reaction.<ref name="Lehninger" />

The half-life of glycine and its elimination from the body varies significantly based on dose.<ref name=":0" /> In one study, the half-life varied between 0.5 and 4.0 hours.<ref name=":0">Template:Cite journal</ref>

Physiological function

The principal function of glycine is it acts as a precursor to proteins. Most proteins incorporate only small quantities of glycine, a notable exception being collagen, which contains about 35% glycine due to its periodically repeated role in the formation of collagen's helix structure in conjunction with hydroxyproline.<ref name="Lehninger">Template:Lehninger4th</ref><ref name="SzpakJAS">Template:Cite journal</ref> In the genetic code, glycine is coded by all codons starting with GG, namely GGU, GGC, GGA and GGG.<ref name=":3" />

As a biosynthetic intermediate

In higher eukaryotes, δ-aminolevulinic acid, the key precursor to porphyrins, is biosynthesized from glycine and succinyl-CoA by the enzyme ALA synthase. Glycine provides the central C₂N subunit of all purines.<ref name="Lehninger" />

As a neurotransmitter

Glycine is an inhibitory neurotransmitter in the central nervous system, especially in the spinal cord, brainstem, and retina. When glycine receptors are activated, chloride enters the neuron via ionotropic receptors, causing an inhibitory postsynaptic potential (IPSP). Strychnine is a strong antagonist at ionotropic glycine receptors, whereas bicuculline is a weak one. Glycine is a required co-agonist along with glutamate for NMDA receptors. In contrast to the inhibitory role of glycine in the spinal cord, this behaviour is facilitated at the (NMDA) glutamatergic receptors which are excitatory.<ref>Template:Cite journal</ref> The Template:LD50 of glycine is 7930 mg/kg in rats (oral),<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and it usually causes death by hyperexcitability.Template:Citation needed

As a toxin conjugation agent

Glycine conjugation pathway has not been fully investigated.<ref>Template:Cite journal</ref> Glycine is thought to be a hepatic detoxifier of a number endogenous and xenobiotic organic acids.<ref>Template:Cite journal</ref> Bile acids are normally conjugated to glycine in order to increase their solubility in water.<ref>Template:Cite journal</ref>

The human body rapidly clears sodium benzoate by combining it with glycine to form hippuric acid which is then excreted.<ref>Template:Cite journal</ref> The metabolic pathway for this begins with the conversion of benzoate by butyrate-CoA ligase into an intermediate product, benzoyl-CoA,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }} Substrate/Product</ref> which is then metabolized by glycine N-acyltransferase into hippuric acid.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }} Substrate/Product</ref>

Uses

In the US, glycine is typically sold in two grades: United States Pharmacopeia ("USP"), and technical grade. USP grade sales account for approximately 80 to 85 percent of the U.S. market for glycine. If purity greater than the USP standard is needed, for example for intravenous injections, a more expensive pharmaceutical grade glycine can be used. Technical grade glycine, which may or may not meet USP grade standards, is sold at a lower price for use in industrial applications, e.g., as an agent in metal complexing and finishing.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Animal and human foods

File:Cu(gly)2(OH2).png

Structure of cis-Cu(glycinate)₂(H₂O)<ref>Template:Cite journal</ref>

Glycine is not widely used in foods for its nutritional value, except in infusions. Instead, glycine's role in food chemistry is as a flavorant. It is mildly sweet, and it counters the aftertaste of saccharine. It also has preservative properties, perhaps owing to its complexation to metal ions. Metal glycinate complexes, e.g. copper(II) glycinate are used as supplements for animal feeds.<ref name=Ull/>

Template:As of, the U.S. Food and Drug Administration "no longer regards glycine and its salts as generally recognized as safe for use in human food",<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and only permits food uses of glycine under certain conditions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Glycine has been researched for its potential to extend life.<ref name=":2">Template:Cite journal</ref><ref>Template:Cite journal</ref> The proposed mechanisms of this effect are its ability to clear methionine from the body, and activating autophagy.<ref name=":2" />

Chemical feedstock

Glycine is an intermediate in the synthesis of a variety of chemical products. It is used in the manufacture of the herbicides glyphosate,<ref>Template:Cite book</ref> iprodione, glyphosine, imiprothrin, and eglinazine.<ref name=Ull/> It is used as an intermediate of antibiotics such as thiamphenicol.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Laboratory research

Glycine is a significant component of some solutions used in the SDS-PAGE method of protein analysis. It serves as a buffering agent, maintaining pH and preventing sample damage during electrophoresis.<ref>Template:Cite journal</ref> Glycine is also used to remove protein-labeling antibodies from Western blot membranes to enable the probing of numerous proteins of interest from SDS-PAGE gel. This allows more data to be drawn from the same specimen, increasing the reliability of the data, reducing the amount of sample processing, and number of samples required.<ref>Template:Cite journal</ref> This process is known as stripping.

Presence in space

The presence of glycine outside the Earth was confirmed in 2009, based on the analysis of samples that had been taken in 2004 by the NASA spacecraft Stardust from comet Wild 2 and subsequently returned to Earth. Glycine had previously been identified in the Murchison meteorite in 1970.<ref>Template:Cite journal</ref> The discovery of glycine in outer space bolstered the hypothesis of so-called soft-panspermia, which claims that the "building blocks" of life are widespread throughout the universe.<ref>Template:Cite news</ref> In 2016, detection of glycine within Comet 67P/Churyumov–Gerasimenko by the Rosetta spacecraft was announced.<ref>Template:Cite news</ref>

The detection of glycine outside the Solar System in the interstellar medium has been debated.<ref name="Snyder">Template:Cite journal</ref>

Evolution

Glycine is proposed to be defined by early genetic codes.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=":1">Template:Cite journal</ref> For example, low complexity regions (in proteins), that may resemble the proto-peptides of the early genetic code are highly enriched in glycine.<ref name=":1" />

Presence in foods

citation

CitationClass=web }}</ref>	Food	Percentage content by weight (g/100g)
Dry unsweetened gelatin powder	19
Snacks, pork skins	11.04
Sesame seeds flour (low fat)	3.43
Beverages, protein powder (soy-based)	2.37
Seeds, safflower seed meal, partially defatted	2.22
Meat, bison, beef and others (various parts)	1.5–2.0
Gelatin desserts	1.96
Seeds, pumpkin and squash seed kernels	1.82
Turkey, all classes, back, meat and skin	1.79
Chicken, broilers or fryers, meat and skin	1.74
Pork, ground, 96% lean / 4% fat, cooked, crumbles	1.71
Bacon and beef sticks	1.64
Peanuts	1.63
Crustaceans, spiny lobster	1.59
Spices, mustard seed, ground	1.59
Salami	1.55
Nuts, butternuts, dried	1.51
Fish, salmon, pink, canned, drained solids	1.42
Almonds	1.42
Fish, mackerel	0.93
Cereals ready-to-eat, granola, homemade	0.81
Leeks, (bulb and lower-leaf portion), freeze-dried	0.7
Cheese, parmesan (and others), grated	0.56
Soybeans, green, cooked, boiled, drained, without salt	0.51
Bread, protein (includes gluten)	0.47
Egg, whole, cooked, fried	0.47
Beans, white, mature seeds, cooked, boiled, with salt	0.38
Lentils, mature seeds, cooked, boiled, with salt	0.37

See also

• Trimethylglycine
• Amino acid neurotransmitter

Further reading

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External links

• Glycine MS Spectrum
• Glycine
• Glycine cleavage system
• Glycine Therapy – A New Direction for Schizophrenia Treatment?
• ChemSub Online (Glycine).
• NASA scientists have discovered glycine, a fundamental building block of life, in samples of comet Wild 2 returned by NASA's Stardust spacecraft.