Glutamine

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Glutamine
L-Glutamin - L-Glutamine.svg
Skeletal formula of L-glutamine
Glutamine-from-xtal-3D-bs-17.png
Glutamine-from-xtal-3D-sf.png
Sample of L-Glutamine.jpg
Names
IUPAC name
Glutamine
Other names
L-Glutamine
(levo)glutamide
2,5-Diamino-5-oxopentanoic acid
2-Amino-4-carbamoylbutanoic acid
Endari [1]
Identifiers
3D model (JSmol)
AbbreviationsGln, Q
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.266 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 200-292-1
KEGG
PubChem CID
UNII
  • InChI=1S/C5H10N2O3/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H2,7,8)(H,9,10)/t3-/m0/s1 Yes check.svgY
    Key: ZDXPYRJPNDTMRX-VKHMYHEASA-N Yes check.svgY
  • O=C(N)CCC(N)C(=O)O
  • Zwitterion:O=C(N)CCC([NH3+])C(=O)[O-]
Properties [2]
C5H10N2O3
Molar mass 146.146 g·mol−1
Melting point decomposes around 185°C
soluble
Acidity (pKa)2.2 (carboxyl), 9.1 (amino)
+6.5º (H2O, c = 2)
Pharmacology
A16AA03 ( WHO )
Supplementary data page
Glutamine (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
L-glutamine oral powder
Clinical data
Trade names Endari, Nutrestore
AHFS/Drugs.com Monograph
MedlinePlus a617035
License data
Routes of
administration
By mouth
Drug class Gastrointestinal agent
ATC code
Legal status
Legal status
Identifiers
  • (S)-2,5-diamino-5-oxopentanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.266 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C5H10N2O3
Molar mass 146.146 g·mol−1
3D model (JSmol)
  • C(CC(=O)N)C(C(=O)O)N
  • InChI=1S/C5H10N2O3/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H2,7,8)(H,9,10)/t3-/m0/s1
  • Key:ZDXPYRJPNDTMRX-VKHMYHEASA-N
Data page
Glutamine (data page)

Glutamine (symbol Gln or Q) [3] is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, polar amino acid. It is non-essential and conditionally essential in humans, meaning the body can usually synthesize sufficient amounts of it, but in some instances of stress, the body's demand for glutamine increases, and glutamine must be obtained from the diet. [4] [5] It is encoded by the codons CAA and CAG.

In human blood, glutamine is the most abundant free amino acid. [6]

The dietary sources of glutamine include especially the protein-rich foods like beef, chicken, fish, dairy products, eggs, vegetables like beans, beets, cabbage, spinach, carrots, parsley, vegetable juices and also in wheat, papaya, Brussels sprouts, celery, kale and fermented foods like miso.

Functions

Glutamine plays a role in a variety of biochemical functions:

Roles in metabolism and cancer

Cancer cells rely on glutamine metabolism as carbon and nitrogen sources. Glutamine level in the blood serum is the highest among other amino acids [13] and is essential for many cellular functions.

Studies have indicated the importance of glutamine in certain tumors. For example, the inhibition of glutamine metabolism was reported to prevent growth of several tumors such as breast, liver, kidney and T-cell lymphoblastic leukemia. [14]

Precursor

Glutamine maintains redox balance by participating in glutathione synthesis and contributing to anabolic processes such as lipid synthesis by reductive carboxylation. [15]

Glutamine also preserves nitrogen availability for synthesis of nucleotides and non-essential amino acids. [16] One of the most important functions of glutamine is its ability to be converted into α-KG, which helps to maintain the flow of the tricarboxylic acid cycle, generating ATPs. [17]

Production

Glutamine is produced industrially using mutants of Brevibacterium flavum , which gives ca. 40 g/L in 2 days using glucose as a carbon source. [18] Glutamine is synthesized by the enzyme glutamine synthetase from glutamate and ammonia. The most relevant glutamine-producing tissue is the muscle mass, accounting for about 90% of all glutamine synthesized. Glutamine is also released, in small amounts, by the lungs and brain. [19] Although the liver is capable of relevant glutamine synthesis, its role in glutamine metabolism is more regulatory than producing, since the liver takes up large amounts of glutamine derived from the gut. [6]

Consumers

The most eager consumers of glutamine are the cells of intestines, [6] the kidney cells for the acid-base balance, activated immune cells, [20] and many cancer cells. [7] [10] [21]

Uses

Nutrition

Glutamine is the most abundant naturally occurring, nonessential amino acid in the human body, and one of the few amino acids that can directly cross the blood–brain barrier. [6] Humans obtain glutamine through catabolism of proteins in foods they eat. [22] In states where tissue is being built or repaired, like growth of babies, or healing from wounds or severe illness, glutamine becomes conditionally essential. [22]

Sickle cell disease

In 2017, the U.S. Food and Drug Administration (FDA) approved L-glutamine oral powder, marketed as Endari, to reduce severe complications of sickle cell disease in people aged five years and older with the disorder. [1]

The safety and efficacy of L-glutamine oral powder were studied in a randomized trial of subjects ages five to 58 years old with sickle cell disease who had two or more painful crises within the 12 months prior to enrollment in the trial. [1] Subjects were assigned randomly to treatment with L-glutamine oral powder or placebo, and the effect of treatment was evaluated over 48 weeks. [1] Subjects who were treated with L-glutamine oral powder experienced fewer hospital visits for pain treated with a parenterally administered narcotic or ketorolac (sickle cell crises), on average, compared to subjects who received a placebo (median 3 vs. median 4), fewer hospitalizations for sickle cell pain (median 2 vs. median 3), and fewer days in the hospital (median 6.5 days vs. median 11 days). [1] Subjects who received L-glutamine oral powder also had fewer occurrences of acute chest syndrome (a life-threatening complication of sickle cell disease) compared with patients who received a placebo (8.6 percent vs. 23.1 percent). [1]

Common side effects of L-glutamine oral powder include constipation, nausea, headache, abdominal pain, cough, pain in the extremities, back pain and chest pain. [1]

L-glutamine oral powder received orphan drug designation. [1] The FDA granted the approval of Endari to Emmaus Medical Inc. [1]

Medical food

Glutamine is marketed as medical food and is prescribed when a medical professional believes a person in their care needs supplementary glutamine due to metabolic demands beyond what can be met by endogenous synthesis or diet. [23]

Safety

Glutamine is safe in adults and in preterm infants. [24] Although glutamine is metabolized to glutamate and ammonia, both of which have neurological effects, their concentrations are not increased much, and no adverse neurological effects were detected. [24] The observed safe level for supplemental L-glutamine in normal healthy adults is 14 g/day. [25]

Adverse effects of glutamine have been prescribed for people receiving home parenteral nutrition and those with liver-function abnormalities. [26] Although glutamine has no effect on the proliferation of tumor cells, it is still possible that glutamine supplementation may be detrimental in some cancer types. [27]

Ceasing glutamine supplementation in people adapted to very high consumption may initiate a withdrawal effect, raising the risk of health problems such as infections or impaired integrity of the intestine. [27]

Structure

Glutamine can exist in either of two enantiomeric forms, L-glutamine and D-glutamine. The L-form is found in nature. Glutamine contains an α-amino group which is in the protonated −NH3+ form under biological conditions and a carboxylic acid group which is in the deprotonated −COO form, known as carboxylate, under physiological conditions.

Glutamine zwitterionic forms at neutral pH: L-glutamine (left) and D-glutamine Betain-Glutamin.png
Glutamine zwitterionic forms at neutral pH: L-glutamine (left) and D-glutamine

Research

Consequences of glutamine depletion in critically ill individuals BMRI2015-545467.001.jpg
Consequences of glutamine depletion in critically ill individuals

Glutamine mouthwash may be useful to prevent oral mucositis in people undergoing chemotherapy but intravenous glutamine does not appear useful to prevent mucositis in the GI tract. [29]

Glutamine supplementation was thought to have potential to reduce complications in people who are critically ill or who have had abdominal surgery but this was based on poor quality clinical trials. [30] Supplementation does not appear to be useful in adults or children with Crohn's disease or inflammatory bowel disease, but clinical studies as of 2016 were underpowered. [12] Supplementation does not appear to have an effect in infants with significant problems of the stomach or intestines. [31]

Some athletes use L-glutamine as supplement. Studies support the positive effects of the chronic oral administration of the supplement on the injury and inflammation induced by intense aerobic and exhaustive exercise, but the effects on muscle recovery from weight training are unclear. [32]

See also

Related Research Articles

α-Ketoglutaric acid Chemical compound

α-Ketoglutaric acid is one of two ketone derivatives of glutaric acid. The term "ketoglutaric acid," when not further qualified, almost always refers to the alpha variant. β-Ketoglutaric acid varies only by the position of the ketone functional group, and is much less common.

<span class="mw-page-title-main">Glutamic acid</span> Amino acid and neurotransmitter

Glutamic acid is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synthesize enough for its use. It is also the most abundant excitatory neurotransmitter in the vertebrate nervous system. It serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABA-ergic neurons.

<span class="mw-page-title-main">Leucine</span> Chemical compound

Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO form under biological conditions), and a side chain isobutyl group, making it a non-polar aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Human dietary sources are foods that contain protein, such as meats, dairy products, soy products, and beans and other legumes. It is encoded by the codons UUA, UUG, CUU, CUC, CUA, and CUG.

<span class="mw-page-title-main">Arginine</span> Amino acid

Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2) and both the amino and guanidino groups are protonated, resulting in a cation. Only the l-arginine (symbol Arg or R) enantiomer is found naturally. Arg residues are common components of proteins. It is encoded by the codons CGU, CGC, CGA, CGG, AGA, and AGG. The guanidine group in arginine is the precursor for the biosynthesis of nitric oxide. Like all amino acids, it is a white, water-soluble solid.

<span class="mw-page-title-main">Ornithine</span> Chemical compound

Ornithine is a non-proteinogenic amino acid that plays a role in the urea cycle. Ornithine is abnormally accumulated in the body in ornithine transcarbamylase deficiency. The radical is ornithyl.

<span class="mw-page-title-main">Glutamate dehydrogenase</span> Hexameric enzyme

Glutamate dehydrogenase is an enzyme observed in both prokaryotes and eukaryotic mitochondria. The aforementioned reaction also yields ammonia, which in eukaryotes is canonically processed as a substrate in the urea cycle. Typically, the α-ketoglutarate to glutamate reaction does not occur in mammals, as glutamate dehydrogenase equilibrium favours the production of ammonia and α-ketoglutarate. Glutamate dehydrogenase also has a very low affinity for ammonia, and therefore toxic levels of ammonia would have to be present in the body for the reverse reaction to proceed. However, in brain, the NAD+/NADH ratio in brain mitochondria encourages oxidative deamination. In bacteria, the ammonia is assimilated to amino acids via glutamate and aminotransferases. In plants, the enzyme can work in either direction depending on environment and stress. Transgenic plants expressing microbial GLDHs are improved in tolerance to herbicide, water deficit, and pathogen infections. They are more nutritionally valuable.

<span class="mw-page-title-main">Glutamine synthetase</span> Class of enzymes

Glutamine synthetase (GS) is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine:

<span class="mw-page-title-main">Branched-chain amino acid</span>

A branched-chain amino acid (BCAA) is an amino acid having an aliphatic side-chain with a branch. Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine, and valine. Non-proteinogenic BCAAs include 2-aminoisobutyric acid.

<span class="mw-page-title-main">Cahill cycle</span> Metabolic pathway for transport of energy into and removal of ammonia from muscles

The Cahill cycle, also known as the alanine cycle or glucose-alanine cycle, is the series of reactions in which amino groups and carbons from muscle are transported to the liver. It is quite similar to the Cori cycle in the cycling of nutrients between skeletal muscle and the liver. When muscles degrade amino acids for energy needs, the resulting nitrogen is transaminated to pyruvate to form alanine. This is performed by the enzyme alanine transaminase (ALT), which converts L-glutamate and pyruvate into α-ketoglutarate and L-alanine. The resulting L-alanine is shuttled to the liver where the nitrogen enters the urea cycle and the pyruvate is used to make glucose.

<span class="mw-page-title-main">Sodium phenylbutyrate</span> Chemical compound

Sodium phenylbutyrate is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an alternative pathway to the urea cycle to allow excretion of excess nitrogen.

<span class="mw-page-title-main">Tumor metabolome</span>

The study of the tumor metabolism, also known as tumor metabolome describes the different characteristic metabolic changes in tumor cells. The characteristic attributes of the tumor metabolome are high glycolytic enzyme activities, the expression of the pyruvate kinase isoenzyme type M2, increased channeling of glucose carbons into synthetic processes, such as nucleic acid, amino acid and phospholipid synthesis, a high rate of pyrimidine and purine de novo synthesis, a low ratio of Adenosine triphosphate and Guanosine triphosphate to Cytidine triphosphate and Uridine triphosphate, low Adenosine monophosphate levels, high glutaminolytic capacities, release of immunosuppressive substances and dependency on methionine.

<span class="mw-page-title-main">Amino acid synthesis</span>

Amino acid synthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids.

<span class="mw-page-title-main">Glutaminase</span>

Glutaminase is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells.

<span class="mw-page-title-main">Phenylacetylglutamine</span> Chemical compound

Phenylacetylglutamine is a product formed by the conjugation of phenylacetate and glutamine. It is a common metabolite that occurs naturally in human urine.

<span class="mw-page-title-main">Omega-amidase</span>

In enzymology, an omega-amidase (EC 3.5.1.3) is an enzyme that catalyzes the chemical reaction

Glutaminolysis (glutamine + -lysis) is a series of biochemical reactions by which the amino acid glutamine is lysed to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.

<i>alpha</i>-Ketoisocaproic acid Chemical compound

α-Ketoisocaproic acid (α-KIC) and its conjugate base, α-ketoisocaproate, are metabolic intermediates in the metabolic pathway for L-leucine. Leucine is an essential amino acid, and its degradation is critical for many biological duties. α-KIC is produced in one of the first steps of the pathway by branched-chain amino acid aminotransferase by transferring the amine on L-leucine onto alpha ketoglutarate, and replacing that amine with a ketone. The degradation of L-leucine in the muscle to this compound allows for the production of the amino acids alanine and glutamate as well. In the liver, α-KIC can be converted to a vast number of compounds depending on the enzymes and cofactors present, including cholesterol, acetyl-CoA, isovaleryl-CoA, and other biological molecules. Isovaleryl-CoA is the main compound synthesized from ɑ-KIC. α-KIC is a key metabolite present in the urine of people with Maple syrup urine disease, along with other branched-chain amino acids. Derivatives of α-KIC have been studied in humans for their ability to improve physical performance during anaerobic exercise as a supplemental bridge between short-term and long-term exercise supplements. These studies show that α-KIC does not achieve this goal without other ergogenicsupplements present as well. α-KIC has also been observed to reduce skeletal muscle damage after eccentrically biased resistance exercises in people who do not usually perform those exercises.

The glutamate–glutamine cycle in biochemistry, is a sequence of events by which an adequate supply of the neurotransmitter glutamate is maintained in the central nervous system. Neurons are unable to synthesize either the excitatory neurotransmitter glutamate, or the inhibitory GABA from glucose. Discoveries of glutamate and glutamine pools within intercellular compartments led to suggestions of the glutamate–glutamine cycle working between neurons and astrocytes. The glutamate/GABA–glutamine cycle is a metabolic pathway that describes the release of either glutamate or GABA from neurons which is then taken up into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as a precursor to the synthesis of either glutamate or GABA.

Juven is a medical food that is manufactured by Abbott Laboratories and used to provide nutritional support under the care of a physician in individuals with muscle wasting due to AIDS or cancer, to promote wound healing following surgery or injury, or when otherwise recommended by a medical professional. It is a powdered nutritional supplement that contains 3 grams of calcium β-hydroxy β-methylbutyrate, 14 grams of L-arginine, and 14 grams of L-glutamine per two daily servings.

<span class="mw-page-title-main">Alanyl-glutamine</span> Chemical compound

Alanyl-glutamine is a chemical compound which in the form L-alanyl-L-glutamine is used in dietary supplementation, in parenteral nutrition, and in cell culture. It is a dipeptide consisting of alanine and glutamine.

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