View source for Glutamic acid

{{chembox
| verifiedrevid = 396143403
| Name = Glutamic acid
| ImageFile = Glutaminsäure - Glutamic acid.svg
| ImageFile1 = L-glutamic-acid-3D-sticks2.png
| ImageSize1 = 180px
| ImageName1 = A representation of the structure of L-glutamic acid
| IUPACName = Glutamic acid
| OtherNames = 2-Aminopentanedioic acid<br/>2-Aminoglutaric acid
| Section1 = {{Chembox Identifiers
|   UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 61LJO5I15S
| InChI = 1/C5H9NO4/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H,7,8)(H,9,10)
|   InChIKey = WHUUTDBJXJRKMK-UHFFFAOYAD
| StdInChI = 1S/C5H9NO4/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H,7,8)(H,9,10)
| StdInChIKey = WHUUTDBJXJRKMK-UHFFFAOYSA-N
| CASNo = 617-65-2
|    CASNo_Ref = {{cascite|correct|CAS}}
|   CASOther = <br/>56-86-0 (<small>L</small>-isomer)<br/>6893-26-1 (<small>D</small>-isomer) <!-- also verified at CAS Common Chemistry -->
|   EC-number = 210-522-2
|   ChemSpiderID = 591
|   PubChem = 611
| IUPHAR_ligand = 1369
|   SMILES = C(CC(=O)O)C(C(=O)O)N
}}
| Section2 = {{Chembox Properties
|   C=5 | H=9 | N=1 | O=4
|   Appearance = white crystalline powder
|   Density = 1.4601 (20 °C)
|   MeltingPt = 199 °C decomp.
|   Solubility = soluble
  }}
| Section7 = {{Chembox Hazards
|   EUIndex = 
|   FlashPt = 
  }}
}}

'''Glutamic acid''' (abbreviated as '''Glu''' or '''E''') is one of the 20 [[proteinogenic amino acid]]s, and its [[codons]] are GAA and GAG. It is a non-[[essential amino acid]]. The [[carboxylate anion]]s and [[salt (chemistry)|salts]] of glutamic acid are known as '''glutamates'''. In [[neuroscience]], glutamate is an important [[neurotransmitter]] which plays a key role in [[long term potentiation]] and is important for learning and memory.<ref name=twsNovK11>{{cite news
 |author= Robert Sapolsky
 |title= Biology and Human Behavior: The Neurological Origins of Individuality, 2nd edition
 |publisher= ''The Teaching Company''
 |quote=see pages 19 and 20 of Guide Book
 |year=2005
 |accessdate= 2010-11-10
}}</ref>

== Chemistry ==
The [[side chain]] [[carboxylic acid]] [[functional group]] has [[acid dissociation constant|pK<sub>a</sub>]] of 4.1 and exists in its [[negatively charged]] [[deprotonation|deprotonated]] [[carboxylate]] form at [[physiological pH]].

== History==
{{Main|Glutamic acid (flavor)}}
Although they occur naturally in many foods, the flavor contributions made by glutamic acid and other amino acids were only scientifically identified early in the twentieth century. The substance was discovered and identified in the year 1866, by the German chemist Karl Heinrich Leopold Ritthausen. In 1907 Japanese researcher [[Kikunae Ikeda]] of the [[Tokyo Imperial University]] identified brown crystals left behind after the evaporation of a large amount of [[kombu]] broth as glutamic acid. These crystals, when tasted, reproduced the ineffable but undeniable flavor he detected in many foods, most especially in seaweed. Professor Ikeda termed this flavor [[umami]]. He then patented a method of mass-producing a crystalline salt of glutamic acid, [[monosodium glutamate]].<ref name="guardian">{{cite news| url=http://observer.guardian.co.uk/foodmonthly/story/0,,1522368,00.html |title = If MSG is so bad for you, why doesn't everyone in Asia have a headache? | publisher = ''[[The Guardian]]''| last = Renton | first = Alex | date = 2005-07-10| accessdate= 2008-11-21}}</ref><ref>{{cite web| url =http://www.jpo.go.jp/seido_e/rekishi_e/kikunae_ikeda.htm | title = Kikunae Ikeda Sodium Glutamate | date= 2002-10-07 | accessdate = 2008-11-21| publisher = [[Japan Patent Office]]}}</ref>

==Biosynthesis==
{| align="left" cellspacing="0" cellpadding="3" style="background: #FFFFFF; border: 1px solid #C0C090;"
! style="background-color: #F8EABA;" | [[Reactants]]
! style="background-color: #F8EABA;" | [[Product (chemistry)|Product]]s
! style="background-color: #F8EABA;" | [[Enzymes]]
|-
| [[Glutamine]] + [[water|H<sub>2</sub>O]] || → '''Glu''' + [[ammonia|NH<sub>3</sub>]]
| [[Protein:GLS|GLS]], [[Protein:GLS2|GLS2]]
|-
| [[N acetylglutamic acid|NAcGlu]] + [[water|H<sub>2</sub>O]] || → '''Glu''' + [[Acetate]]
| (unknown)
|-
| [[Alpha-Ketoglutaric acid|α-ketoglutarate]] + [[NADP]]H + NH<sub>4</sub><sup>+</sup> || → '''Glu''' + [[NADP]]<sup>+</sup> + H<sub>2</sub>O
| [[Protein:GLUD1|GLUD1]], [[Protein:GLUD2|GLUD2]]
|-
| [[Alpha-Ketoglutaric acid|α-ketoglutarate]] + [[amino acid|α-amino acid]] || → '''Glu''' + [[oxoacid|α-oxo acid]]
| [[transaminase]]
|-
| [[1-Pyrroline-5-carboxylate]] + [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]] + H<sub>2</sub>O || → '''Glu''' + NADH
| [[Protein:ALDH4A1|ALDH4A1]]
|-
| [[N-formimino-L-glutamate]] + [[Folic acid|FH<sub>4</sub>]] || →  '''Glu''' + [[Folic acid|5-formimino-FH<sub>4</sub>]]
| [[Protein:FTCD|FTCD]]
|-
|}
<br clear="left"/>

== Function and uses ==
=== Metabolism ===
Glutamate is a key molecule in cellular [[metabolism]]. In humans, dietary [[proteins]] are broken down by digestion into [[amino acids]], which serve as metabolic fuel for other functional roles in the body. A key process in amino acid degradation is [[transamination]], in which the amino group of an amino acid is transferred to an α-ketoacid, typically catalysed by a [[transaminase]]. The reaction can be generalised as such:

: R<sub>1</sub>-amino acid + R<sub>2</sub>-α-ketoacid {{unicode|&#8652;}} R<sub>1</sub>-α-ketoacid + R<sub>2</sub>-amino acid

A very common α-keto acid is α-ketoglutarate, an intermediate in the [[citric acid cycle]]. Transamination of α-ketoglutarate gives glutamate. The resulting α-ketoacid product is often a useful one as well, which can contribute as fuel or as a substrate for further metabolism processes. Examples are as follows:

: [[Alanine]] + α-ketoglutarate {{unicode|&#8652;}} [[pyruvate]] + glutamate

: [[Aspartate]] + α-ketoglutarate {{unicode|&#8652;}} [[oxaloacetate]] + glutamate

Both pyruvate and oxaloacetate are key components of cellular metabolism, contributing as substrates or intermediates in fundamental processes such as [[glycolysis]], [[gluconeogenesis]], and the [[citric acid cycle]].

Glutamate also plays an important role in the body's disposal of excess or waste [[nitrogen]]. Glutamate undergoes [[deamination]], an oxidative reaction catalysed by [[glutamate dehydrogenase]], as follows:

: glutamate + H<sub>2</sub>O + [[Nicotinamide adenine dinucleotide phosphate|NADP]]<sup>+</sup> → α-ketoglutarate + [[Nicotinamide adenine dinucleotide phosphate|NADPH]] + NH<sub>3</sub> + H<sup>+</sup>

Ammonia (as [[ammonium]]) is then excreted predominantly as [[urea]], synthesised in the [[liver]]. Transamination can, thus, be linked to deamination, effectively allowing nitrogen from the amine groups of amino acids to be removed, via glutamate as an intermediate, and finally excreted from the body in the form of urea.

=== Neurotransmitter ===
Glutamate is the most abundant excitatory [[neurotransmitter]] in the vertebrate [[nervous system]]. At [[synapses|chemical synapses]], glutamate is stored in vesicles. [[Nerve impulses]] trigger release of glutamate from the pre-synaptic cell. In the opposing post-synaptic cell, [[glutamate receptors]], such as the [[NMDA receptor]], bind glutamate and are activated. Because of its role in [[synaptic plasticity]], glutamate is involved in cognitive functions like [[learning]] and [[memory]] in the brain.<ref>{{cite journal |author=McEntee, W. & Crook, T |title=Glutamate: its role in learning, memory, and the aging brain. |journal=Psychopharmacology |volume=111 |issue=4 |pages=391–401 |year=1993 |pmid=7870979 |url=http://www.ncbi.nlm.nih.gov/pubmed/7870979 |doi=10.1007/BF02253527}}</ref>  The form of plasticity known as [[long-term potentiation]] takes place at glutamatergic synapses in the [[hippocampus]], [[neocortex]], and other parts of the brain. Glutamate works not only as a point-to-point transmitter but also through spill-over synaptic crosstalk between synapses in which summation of glutamate released from a neighboring synapse creates extrasynaptic signaling/[[volume transmission]].<ref>Okubo Y, Sekiya H, Namiki S, Sakamoto H, Iinuma S, Yamasaki M, Watanabe M, Hirose K, Iino M. (2010). Imaging extrasynaptic glutamate dynamics in the brain. Proc Natl Acad Sci U S A. 107:6526–6531. {{doi|10.1073/pnas.0913154107}} PMID 20308566</ref>

[[Glutamate transporter]]s<ref>{{cite journal |author=Shigeri Y, Seal RP, Shimamoto K |title=Molecular pharmacology of glutamate transporters, EAATs and VGLUTs |journal=Brain Res. Brain Res. Rev. |volume=45 |issue=3 |pages=250–65 |year=2004 |month=July |pmid=15210307 |doi=10.1016/j.brainresrev.2004.04.004 |url=}}</ref> are found in [[neuron]]al and [[glia]]l membranes. They rapidly remove glutamate from the [[extracellular]] space. In brain injury or disease, they can work in reverse, and excess glutamate can accumulate outside cells. This process causes calcium ions to enter cells via [[NMDA receptor]] channels, leading to neuronal damage and eventual cell death, and is called [[excitotoxicity]]. The mechanisms of [[apoptosis|cell death]] include

* Damage to [[mitochondria]] from excessively high intracellular [[Calcium|Ca<sup>2+</sup>]]<ref>{{cite journal |author=Manev H, Favaron M, Guidotti A, Costa E |title=Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death |journal=Mol. Pharmacol. |volume=36 |issue=1 |pages=106–12 |year=1989 |month=July |pmid=2568579 |doi= |url=http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2568579}}</ref>

* Glu/Ca<sup>2+</sup>-mediated promotion of [[transcription factor]]s for pro-apoptotic genes, or downregulation of transcription factors for anti-apoptotic genes

Excitotoxicity due to glutamate occurs as part of the [[ischemic cascade]] and is associated with [[stroke]]<ref name=twsNovK11/> and diseases like [[amyotrophic lateral sclerosis]], [[lathyrism]], [[autism]], some forms of mental retardation, and [[Alzheimer's disease]].<ref>{{cite journal |author=Hynd MR, Scott HL, Dodd PR. |title=Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. |journal=Neurochem Int. |volume=45 |issue=5 |pages=583–95 |year=2004 |month=October |pmid=15234100 |doi= 10.1016/j.neuint.2004.03.007|url=http://www.ncbi.nlm.nih.gov/pubmed/15234100}}</ref><ref name=twsNovK11/>

Glutamic acid has been implicated in epileptic [[seizure]]s. Microinjection of glutamic acid into neurons produces spontaneous [[depolarisation]]s around one [[second]] apart, and this firing pattern is similar to what is known as [[paroxysmal depolarizing shift]] in epileptic attacks. This change in the resting membrane potential at seizure foci could cause spontaneous opening of [[VOCC|voltage-activated calcium channel]]s, leading to glutamic acid release and further depolarization.

Experimental techniques to detect glutamate in intact cells include using a genetically-engineered [[nanosensor]].<ref>{{cite journal | author=Okumoto, S., ''et al.'' | title=Detection of glutamate release from neurons by genetically encoded surface-displayed FRET nanosensors | journal=Proceedings of the National Academy of Sciences U.S.A | volume=102 | issue=24 | year=2005 | pages=8740–8745 | pmid=15939876 | doi = 10.1073/pnas.0503274102 | pmc = 15939876}}</ref> The sensor is a fusion of a glutamate-binding protein and two fluorescent proteins. When glutamate binds, the fluorescence of the sensor under [[ultraviolet]] light changes by [[fluorescence resonance energy transfer|resonance between the two fluorophores]]. Introduction of the nanosensor into cells enables optical detection of the glutamate concentration. Synthetic analogs of glutamic acid that can be activated by [[ultraviolet]] light and [[two-photon excitation microscopy]] have also been described.<ref>{{cite journal | author=Ellis-Davies, G.C.R., ''et al.'' | title=4- 
Carboxymethoxy-5,7-dinitroindolinyl-Glu: an improved caged glutamate for expeditious ultra-violet and 2-photon photolysis in brain slices | journal=Journal of Neuroscience | volume=27 | year=2007 | issue=June | pages=6601–6604 | pmid=17581946 | doi=10.1523/JNEUROSCI.1519-07.2007}}</ref> This method of rapidly uncaging by [[photostimulation]] is useful for mapping the connections between neurons, and understanding synapse function.

Evolution of glutamate receptors is entirely the opposite in invertebrates, in particular, arthropods and nematodes, where glutamate stimulates glutamate-gated chloride channels.  The beta subunits of the receptor respond with very high affinity to glutamate and glycine.<ref>Laughton, D.L., Wheeler, S.V., Lunt, G.G. and Wolstenholme, A.J. 1995. "The beta-subunit of ''Caenorhabditis elegans'' avermectin receptor responds to glycine and is encoded by chromosome 1". ''J. Neurochem.'' 64, 2354-2357</ref> Targeting these receptors has been the therapeutic goal of [[anthelmintic]] therapy using [[avermectin]]s.  Avermectins target the alpha-subunit of glutamate-gated chloride channels with high affinity.<ref>Cully, D.F., Vassilatis, D.K., Liu, K.K., Paress, P.S., Van der Ploeg, L.H.T., Schaeffer, J.M. and Arena, J.P.  1994.  "Cloning of an avermectin-sensitive glutamate gated choride channels from ''Caenorhabditis elegans''".  ''Nature'' 371, 707-711</ref> These receptors have also been described in arthropods, such as ''Drosophila melanogaster''<ref>Cully, D.F., Paress, P.S., Liu, K.K., Schaeffer, J.M. and Arena, J.P. 1996.  "Identification of a ''Drosophila melanogaster'' glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin". ''J. Biol. Chem. '271, 20187-20191'</ref> and ''Lepeophtheirus salmonis''.<ref>Tribble, N.D., Burka, J.F. and Kibenge, F.S.B. 2007.  "Identification of the genes encoding for putative gamma aminobutyric acid (GABA) and glutamate-gated chloride channel (GluCl) alpha receptor subunits in sea lice (''Lepeophtheirus salmonis'')".  ''J. Vet. Pharmacol. Ther.'' 30, 163-167</ref> Irreversible activation of these receptors with avermectins results in hyperpolarization at synapses and neuromuscular junctions resulting in flaccid paralysis and death of nematodes and arthropods.

[[File:L-Glutamate Structural Formulae.png|thumb|right|250px||L-Glutamate at physiological conditions]]

=== Brain nonsynaptic glutamatergic signaling circuits ===
Extracellular glutamate in ''[[Drosophila]]'' brains has been found to regulate postsynaptic glutamate receptor clustering, via a process involving receptor desensitization.<ref name = augustin>{{cite journal | author=Augustin H, Grosjean Y, Chen K, Sheng Q, Featherstone DE | title=Nonvesicular release of glutamate by glial xCT transporters suppresses glutamate receptor clustering in vivo | journal=Journal of Neuroscience | volume=27 | issue=1 | year=2007 | pages=111–123 | pmid=17202478 | doi = 10.1523/JNEUROSCI.4770-06.2007 | pmc=2193629}}</ref> A gene expressed in [[glial cell]]s actively transports glutamate into the [[extracellular space]],<ref name = augustin/> while in the [[nucleus accumbens]] stimulating group II metabotropic glutamate receptors, this gene was found to reduce extracellular glutamate levels.<ref>{{cite journal | author=Zheng Xi, Baker DA, Shen H, Carson DS, Kalivas PW | title=Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens | journal=Journal of Pharmacology and Experimental Therapeutics | volume=300 | issue=1 | year=2002 | pages=162–171 | pmid=11752112 | doi=10.1124/jpet.300.1.162}}</ref> This raises the possibility that this extracellular glutamate plays an "endocrine-like" role as part of a larger homeostatic system.

==== GABA precursor ====
Glutamate also serves as the precursor for the synthesis of the inhibitory [[GABA]] in GABA-ergic neurons. This reaction is catalyzed by  [[glutamate decarboxylase]] (GAD), which is most abundant in the [[cerebellum]] and [[pancreas]].

[[Stiff-man syndrome]] is a neurologic disorder caused by anti-GAD antibodies, leading to a decrease in GABA synthesis and, therefore, impaired motor function such as muscle stiffness and spasm. Since the pancreas is also abundant for the enzyme GAD, a direct immunological destruction occurs in the pancreas and the patients will have diabetes mellitus.

=== Flavor enhancer ===
{{Main|Glutamic acid (flavor)}}
Free glutamic acid is present in a wide variety of foods, including [[cheese]] and [[soy sauce]], and is responsible for [[umami]], one of the five [[basic taste]]s of the human sense of [[taste]]. Glutamic acid is often used as a [[food additive]] and [[flavour enhancer]] in the form of its [[sodium]] [[salt]] [[monosodium glutamate]] (MSG).

=== Nutrient ===
All meats, poultry, fish, eggs, dairy products, as well as [[kombu]] are excellent sources of glutamic acid. Some protein-rich plant foods also serve as sources.  Thirty to 35% of the protein in wheat is glutamic acid. Ninety-five percent of the dietary glutamate is metabolized by intestinal cells in a first pass.<ref>{{cite journal | author=Reeds, P.J., ''et al.'' | title=Intestinal glutamate metabolism | journal=Journal of Nutrition | volume=130 | issue=4s | date=1 April 2000| pages=978S–982S | pmid=10736365 | url = http://jn.nutrition.org/cgi/content/full/130/4/978S }}</ref>

=== Plant growth ===
[[Auxigro]] is a plant growth preparation that contains 30% glutamic acid.

== Production ==
China-based [[Fufeng Group]] Limited is the largest producer of glutamic acid in the world, with capacity increasing to 300,000 tons at the end of 2006 from 180,000 tons during 2006, putting them at 25%&ndash;30% of the Chinese market. Meihua is the second-largest Chinese producer. Together, the top-five producers have roughly 50% share in China. Chinese demand is roughly 1.1 million tons per year, while global demand, including China, is 1.7 million tons per year.

== Pharmacology ==
The drug [[phencyclidine]] (more commonly known as PCP) [[Receptor antagonist|antagonizes]] glutamic acid non-competitively at the NMDA receptor. For the same reasons, sub-anaesthetic doses of [[ketamine]] have strong dissociative and hallucinogenic effects. Glutamate does not easily pass the [[blood brain barrier]], but, instead, is transported by a high-affinity transport system.<ref>{{cite journal |author=Smith QR |title=Transport of glutamate and other amino acids at the blood-brain barrier |journal=J. Nutr. |volume=130 |issue=4S Suppl |pages=1016S–22S |year=2000 |month=April |pmid=10736373 |doi= |url=http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=10736373}}</ref> It can also be converted into [[glutamine]].

==See also==
*[[Kainic acid]]
*[[Disodium glutamate]]
*[[Monosodium glutamate]]

== References ==
{{Commons category|Glutamic acid}}
{{Reflist|2}}

==Further reading==
* {{Lehninger4th}}

{{AminoAcids}}
{{Glutamatergics}}
{{Amino acid metabolism intermediates}}
{{Neurotransmitters}}
{{Neurotoxins}}

{{DEFAULTSORT:Glutamic Acid}}
[[Category:Amino acids]]
[[Category:Proteinogenic amino acids]]
[[Category:Glucogenic amino acids]]
[[Category:Acidic amino acids]]
[[Category:Dicarboxylic acids]]
[[Category:Neurotransmitters]]
[[Category:Flavour enhancers]]
[[Category:Umami enhancers]]
[[Category:Glutamates]]

[[bn:গ্লুটামিক অ্যাসিড]]
[[zh-min-nan:Glutamine sng]]
[[ca:Àcid glutàmic]]
[[cs:Kyselina glutamová]]
[[da:Glutaminsyre]]
[[de:Glutaminsäure]]
[[es:Ácido glutámico]]
[[eo:Glutama acido]]
[[eu:Azido glutamiko]]
[[fa:اسید گلوتامیک]]
[[fr:Acide glutamique]]
[[ko:글루탐산]]
[[id:Asam glutamat]]
[[it:Acido glutammico]]
[[he:חומצה גלוטמית]]
[[lv:Glutamīnskābe]]
[[lb:Glutamat]]
[[lt:Glutamo rūgštis]]
[[hu:Glutaminsav]]
[[nl:Glutaminezuur]]
[[ja:グルタミン酸]]
[[no:Glutaminsyre]]
[[oc:Acid glutamic]]
[[pl:Kwas glutaminowy]]
[[pt:Ácido glutâmico]]
[[ru:Глутаминовая кислота]]
[[sk:Kyselina glutámová]]
[[sl:Glutaminska kislina]]
[[sr:Glutaminska kiselina]]
[[fi:Glutamiinihappo]]
[[sv:Glutaminsyra]]
[[ta:குளூட்டாமிக் காடி]]
[[th:กลูตาเมต]]
[[tr:Glutamik asit]]
[[uk:Глутамінова кислота]]
[[zh:穀氨酸]]