The AtlasAmino acidsPolar, uncharged
GlutamineGln · Q
The most abundant free amino acid in the body, the carrier of nitrogen between organs, and a supplement that, given to the critically ill in the largest trial, raised mortality.
Molecule · Gln · 10 heavy atoms
Glutamine
C5H10N2O3146.15 g/mol
The most abundant free amino acid in the body, the carrier of nitrogen between organs, and a supplement that, given to the critically ill in the largest trial, raised mortality.
Built fromthe charted ones open their own entry
- Codes
- Gln · Q
- Formula
- C5H10N2O3
- Molar mass
- 146.15 g/mol
- Systematic name
- (2S)-2,5-diamino-5-oxopentanoic acid
- Side chain
- 2-Carbamoylethyl: two carbons and an amide; polar and uncharged.
- Class
- Polar, uncharged
- In the diet
- Conditionally essential
- Carbon skeleton
- Glucogenic
- pKa
- α-COOH 2.17 · α-NH3+ 9.13
- Isoelectric point
- pH 5.65
- Hydropathy
- -3.5 (Kyte–Doolittle)
- Codons
CAACAG
pKa and isoelectric point: Nelson and Cox, Lehninger Principles of Biochemistry, table of amino acid properties (free amino acid, 25 °C). Hydropathy: Kyte and Doolittle, J Mol Biol 1982. Essentiality: Reeds, J Nutr 2000. Formula and mass computed from the structure.
In brief
What it is
Glutamate with its side-chain acid turned into an amide, which makes it neutral and gives it a second nitrogen to carry. It is the most abundant and versatile free amino acid in the body 1.
Why it matters
Glutamine moves nitrogen between tissues, fuels the gut lining and dividing immune cells, lets the kidney excrete acid as ammonium, and keeps the brain’s glutamate and GABA supplies topped up 2,3. That centrality is why it was proposed as conditionally essential in critical illness 2.
Where it runs short
Plasma glutamine falls in acute illness, which led to the idea that the body cannot make enough under stress 2,4. Inherited inability to make it is catastrophic: two newborns without glutamine synthetase had almost no glutamine in blood, urine or spinal fluid, severe brain malformations and died 5.
Where it turns
In the largest trial, 1,223 critically ill adults given glutamine had higher mortality at 28 days, in hospital and at six months than those who were not 6.
A low level in illness was taken as a deficiency to correct. The trials said otherwise.
The molecule
Glutamine is glutamate with its side-chain carboxylic acid replaced by an amide, –CONH₂. The change removes the negative charge and adds a second nitrogen, which is the point: glutamine is how the body carries nitrogen in a safe, non-toxic form.
Move across the chart to read the charge at any pH.
Computed from its pKa values (α-carboxyl 2.17, α-amino 9.13) by the Henderson–Hasselbalch equation, for the free amino acid in water at 25 °C. Inside a folded protein the same groups can shift by a unit or more. The faint lines are the other amino acids.
Kyte–Doolittle hydropathy index: positive values avoid water and tend to be buried inside a folded protein, negative values sit on its surface. Each letter is an amino acid; choose one to open it.
| 1st ↓ 2nd → | U | C | A | G | 3rd |
|---|---|---|---|---|---|
| U | UUUPhe | UCUSer | UAUTyr | UGUCys | U |
| UUCPhe | UCCSer | UACTyr | UGCCys | C | |
| UUALeu | UCASer | UAAStop | UGAStop | A | |
| UUGLeu | UCGSer | UAGStop | UGGTrp | G | |
| C | CUULeu | CCUPro | CAUHis | CGUArg | U |
| CUCLeu | CCCPro | CACHis | CGCArg | C | |
| CUALeu | CCAPro | CAAGln | CGAArg | A | |
| CUGLeu | CCGPro | CAGGln | CGGArg | G | |
| A | AUUIle | ACUThr | AAUAsn | AGUSer | U |
| AUCIle | ACCThr | AACAsn | AGCSer | C | |
| AUAIle | ACAThr | AAALys | AGAArg | A | |
| AUGMet | ACGThr | AAGLys | AGGArg | G | |
| G | GUUVal | GCUAla | GAUAsp | GGUGly | U |
| GUCVal | GCCAla | GACAsp | GGCGly | C | |
| GUAVal | GCAAla | GAAGlu | GGAGly | A | |
| GUGVal | GCGAla | GAGGlu | GGGGly | G |
Where it comes from
Glutamine synthetase builds glutamine from glutamate and ammonia, using ATP 5. Muscle makes and exports most of the body’s supply, and glutamine is the most abundant free amino acid in blood and tissue 1.
Much of what is swallowed never reaches the body. In adults given labelled glutamine through a nasogastric tube, 54% was taken up by the gut and liver on first pass 7, and in infants oral glutamine is essentially all used by the splanchnic tissues 4. It is also unstable in solution, which is why it is not routinely added to intravenous amino acid mixtures 4.
Conditionally essentialMade from glutamate and ammonia by glutamine synthetase in most tissues, so it is not needed in the diet; it was proposed as conditionally essential in critical illness, a proposal the largest trials did not support 2,4,6.
How much
None set; the body makes it 4.
In the bottle · fermentedMade by fermentation in engineered Corynebacterium glutamicum, now at titres above 70 g per litre, for food, medicine and feed 8,9.
What the body does with it
Rapidly dividing cells use glutamine as a fuel, especially the cells lining the gut and lymphocytes 2. Immune cells consume it at rates similar to or greater than glucose, and it is needed for lymphocyte proliferation, macrophage activity and neutrophil killing in laboratory studies 1.
In the kidney, glutamine is the source of the ammonia that carries acid out as ammonium, and that output rises in acidosis 2,10.
In the brain, the glutamate–glutamine cycle runs between astrocytes and neurons: astrocytes take up released glutamate, make it into glutamine, and send it back to neurons to rebuild their transmitter stores. The same reaction disposes of ammonia in the brain 3.
Many cancer cells are “addicted” to glutamine, despite being able to make it: they use it to import essential amino acids, keep mTOR active, and fuel their mitochondria and NADPH production 11.
In three sentences each
A nitrogen carrier
Glutamine carries two nitrogens, one in its amino group and one in its amide; muscle, gut, liver and kidney trade it to move nitrogen and to build nucleotides, amino sugars and other amino acids 1,2.
Acid out as ammonium
The kidney splits glutamine to release ammonia, which carries acid into the urine as ammonium, and the proximal tubule steps this up in metabolic acidosis 2,10.
The brain’s supply line
Astrocytes make large amounts of glutamine and pass it to neurons, which turn it back into glutamate and GABA; diminished astrocyte glutamine synthesis is a common thread in neurological disease 3.
How it is made, moved and broken down
Glutaminase turns glutamine into glutamate and ammonia, the first step towards fuel and the kidney’s ammonium 2,12. Blocking that enzyme was a long-standing hope in cancer, but the glutamine antagonist DON was stopped for toxicity, and the glutaminase inhibitor telaglenastat did not improve treatment of kidney cancer 12,13.
Carbon skeleton · glucogenicGlutaminase converts it to glutamate and then 2-oxoglutarate, which enters the Krebs cycle; in many cancer cells it is the main mitochondrial fuel 11,12.
- Glutamate + NH₄⁺
- Glutamine synthetaseGLUL · ATP
- Glutamine
- GlutaminaseGLS, GLS2
- Glutamate + NH₄⁺
- Glutamate released by neurons
- Glutamine synthetaseGLUL · ATP
- Glutamine in astrocytes
- Glutaminase, then GADGLS, GAD1 · vitamin B6 for GAD
- Glutamate, and GABA
Where it matters most
When it goes wrong
Drug
Glutamine supplements in critical illness
In REDOXS, 1,223 ventilated adults with multi-organ failure were given glutamine, antioxidants, both or neither; glutamine raised in-hospital and six-month mortality and did nothing for organ failure or infection 6. In MetaPlus, a feed enriched with glutamine, fish oil, selenium and antioxidants did not reduce infections, and six-month mortality in medical patients was 54% against 35% 14.
Drug
Sickle cell disease
HBB
In a phase 3 trial of 230 patients, pharmaceutical-grade L-glutamine twice daily cut the median number of pain crises over 48 weeks from 4.0 to 3.0 and hospitalisations from 3.0 to 2.0 15. A systematic review found the three eligible studies supportive but with conflicting results and limitations 16.
Inherited
Congenital glutamine synthetase deficiency
GLUL · autosomal recessive
Two unrelated newborns with homozygous GLUL mutations had virtually no glutamine in serum, urine and cerebrospinal fluid, severe brain malformations and multi-organ failure, and died in the neonatal period 5.
How it is foundPlasma, urine and CSF amino acids; GLUL sequencing 5.
Drug
Cancer and glutamine
GLS
Many cancer cells consume glutamine heavily 11. The glutamine antagonist DON worked in early studies but was halted for toxicity; prodrugs designed to reach the brain are in preclinical work 13. The glutaminase inhibitor telaglenastat did not add to cabozantinib in 444 people with kidney cancer 12.
How it is measured
Plasma glutamine is routinely measured but hard to measure well. It breaks down in solution, and in electrospray mass spectrometry it cyclises to pyroglutamate inside the instrument; separating glutamine, glutamate and pyroglutamate and using isotope-labelled standards corrects the error 4,17.
- Plasma glutaminePart of the amino acid panel; low in critical illness and very low in glutamine synthetase deficiency 4,5.A low plasma level was not a reliable guide to who would benefit from supplements 1. In electrospray mass spectrometry, a third to nearly all of the glutamine can cyclise to pyroglutamate inside the instrument unless the method corrects for it 17.
Food, supplements and the evidence
Establishedreplicated in people, for a named outcome
- Pharmaceutical L-glutamine reduces pain crises modestly in sickle cell disease 15.
Uncertainsmall, short, mixed, surrogate or preclinical
- Glutamine for post-infectious, diarrhoea-predominant irritable bowel syndrome: a single-centre trial of 5 g three times a day in 106 completers reported responses in 80% against 6% on placebo, an effect large enough to need replication 18.
- Glutamine for athletes and immune support: laboratory roles in immune cells are clear, but whether supplements help is difficult to determine 1.
What is strange about it
Glutamine’s reputation in intensive care was built on the logic that low levels in illness meant a shortage 2. The REDOXS trial, the largest test of it, found a trend to higher 28-day mortality, 32.4% against 27.2%, and significantly higher mortality in hospital and at six months 6.
The only drug use of glutamine with regulatory approval is in sickle cell disease, approved by the FDA in 2017 on a trial in which the median number of pain crises over 48 weeks fell from four to three 15,16.
Tumours that depend on glutamine made glutaminase an obvious target; in 444 people with kidney cancer, adding the glutaminase inhibitor telaglenastat changed median progression-free survival from 9.3 to 9.2 months 12.
Where it connects
In the Atlas
On the map
A star in Conditional amino acids, one of 14. The most abundant free amino acid in the body and conditionally essential in critical illness — where giving extra of it, in the largest trial, increased mortality.
Sources
18 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.
- 1Cruzat V, Macedo Rogero M, Noel Keane K, et al. Glutamine: metabolism and immune function, supplementation and clinical translation.doi:10.3390/nu10111564 · PMID 30360490
Review; the most abundant free amino acid; immune roles.
- 2Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid?doi:10.1111/j.1753-4887.1990.tb02967.x · PMID 2080048
The original argument for conditional essentiality.
- 3Andersen JV, Schousboe A. Glial glutamine homeostasis in health and disease.doi:10.1007/s11064-022-03771-1 · PMID 36322369
Astrocyte glutamine and the glutamate–glutamine cycle.
- 4Parimi PS, Kalhan SC. Glutamine supplementation in the newborn infant.doi:10.1016/j.siny.2006.10.003 · PMID 17142118
Oral glutamine used by splanchnic tissues; unstable in solution.
- 5Häberle J, Görg B, Rutsch F, et al. Congenital glutamine deficiency with glutamine synthetase mutations.doi:10.1056/NEJMoa050456 · PMID 16267323
Two newborns.
- 6Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients.doi:10.1056/NEJMoa1212722 · PMID 23594003
REDOXS: 1,223 patients; harm with glutamine.
- 7Matthews DE, Marano MA, Campbell RG. Splanchnic bed utilization of glutamine and glutamic acid in humans.doi:10.1152/ajpendo.1993.264.6.E848 · PMID 8101428
54% of enteral glutamine retained on first pass.
- 8Lv Q, Hu M, Tian L, et al. Enhancing L-glutamine production in Corynebacterium glutamicum by rational metabolic engineering combined with a two-stage pH control strategy.doi:10.1016/j.biortech.2021.125799 · PMID 34425465
73.5 g/L.
- 9EFSA FEEDAP Panel; Bampidis V, Azimonti G, et al. Safety and efficacy of L-glutamine produced using Corynebacterium glutamicum NITE BP-02524 for all animal species.doi:10.2903/j.efsa.2020.6075 · PMID 32874286
Fermentation with a genetically modified strain; no viable cells in product.
- 10Curthoys NP, Moe OW. Proximal tubule function and response to acidosis.doi:10.2215/CJN.10391012 · PMID 23908456
The proximal tubule’s response to acidosis.
- 11Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer.doi:10.1016/j.tibs.2010.05.003 · PMID 20570523
Why cancer cells consume glutamine.
- 12Tannir NM, Agarwal N, Porta C, et al. Efficacy and safety of telaglenastat plus cabozantinib vs placebo plus cabozantinib in patients with advanced renal cell carcinoma: the CANTATA randomized clinical trial.doi:10.1001/jamaoncol.2022.3511 · PMID 36048457
444 patients; no benefit. Manufacturer-sponsored.
- 13Rais R, Jančařík A, Tenora L, et al. Discovery of 6-diazo-5-oxo-L-norleucine (DON) prodrugs with enhanced CSF delivery in monkeys: a potential treatment for glioblastoma.doi:10.1021/acs.jmedchem.6b01069 · PMID 27560860
DON halted for toxicity; prodrugs preclinical.
- 14van Zanten AR, Sztark F, Kaisers UX, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial.doi:10.1001/jama.2014.7698 · PMID 25096691
MetaPlus: 301 patients; no fewer infections; higher six-month mortality in medical patients. Manufacturer co-authors.
- 15Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of L-glutamine in sickle cell disease.doi:10.1056/NEJMoa1715971 · PMID 30021096
230 patients, 48 weeks.
- 16Cieri-Hutcherson NE, Hutcherson TC, Conway-Habes EE, et al. Systematic review of L-glutamine for prevention of vaso-occlusive pain crisis in patients with sickle cell disease.doi:10.1002/phar.2329 · PMID 31505045
FDA approval in 2017; three eligible studies.
- 17Purwaha P, Silva LP, Hawke DH, et al. An artifact in LC-MS/MS measurement of glutamine and glutamic acid: in-source cyclization to pyroglutamic acid.doi:10.1021/ac501451v · PMID 24892977
In-source conversion to pyroglutamate.
- 18Zhou Q, Verne ML, Fields JZ, et al. Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome.doi:10.1136/gutjnl-2017-315136 · PMID 30108163
Single centre; 79.6% against 5.8% responders.
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