Glutamic acid (symbolGlu orE;[4] known asglutamate in its anionic form) is an α-amino acid that is used by almost all living beings in thebiosynthesis ofproteins. It is anon-essential nutrient for humans, meaning that the human body can synthesize enough for its use. It is also the most abundant excitatoryneurotransmitter in the vertebratenervous system. It serves as the precursor for the synthesis of the inhibitorygamma-aminobutyric acid (GABA) in GABAergic neurons.
Its molecular formula isC 5H 9NO 4. Glutamic acid exists in two optically isomeric forms; thedextrorotatoryL-form is usually obtained by hydrolysis ofgluten or from the waste waters ofbeet-sugar manufacture or by fermentation.[5][full citation needed] Its molecular structure could be idealized as HOOC−CH(NH 2)−(CH 2)2−COOH, with twocarboxyl groups −COOH and oneamino group −NH 2. However, in the solid state and mildlyacidic water solutions, the molecule assumes anelectrically neutralzwitterion structure−OOC−CH(NH+ 3)−(CH 2)2−COOH. It isencoded by thecodons GAA or GAG.
When glutamic acid is dissolved in water, theamino group (−NH 2) may gain aproton (H+ ), and/or thecarboxyl groups may lose protons, depending on theacidity of the medium.
In sufficiently acidic environments, both carboxyl groups are protonated and the molecule becomes acation with a single positive charge, HOOC−CH(NH+ 3)−(CH 2)2−COOH.[8]
AtpH values between about 2.5 and 4.1,[8] the carboxylic acid closer to the amine generally loses a proton, and the acid becomes the neutral zwitterion−OOC−CH(NH+ 3)−(CH 2)2−COOH. This is also the form of the compound in the crystalline solid state.[9][10] The change in protonation state is gradual; the two forms are in equal concentrations at pH 2.10.[11]
At even higher pH, the other carboxylic acid group loses its proton and the acid exists almost entirely as the glutamate anion−OOC−CH(NH+ 3)−(CH 2)2−COO−, with a single negative charge overall. The change in protonation state occurs at pH 4.07.[11] This form with both carboxylates lacking protons is dominant in thephysiological pH range (7.35–7.45).
At even higher pH, the amino group loses the extra proton, and the prevalent species is the doubly-negative anion−OOC−CH(NH 2)−(CH 2)2−COO−. The change in protonation state occurs at pH 9.47.[11]
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 20th century. The substance was discovered and identified in the year 1866 by the German chemistKarl Heinrich Ritthausen, who treated wheatgluten (for which it was named) withsulfuric acid.[14] In 1908, Japanese researcherKikunae Ikeda of theTokyo Imperial University identified brown crystals left behind after the evaporation of a large amount ofkombu broth as glutamic acid. These crystals, when tasted, reproduced the novel flavor he detected in many foods, most especially in seaweed. Professor Ikeda termed this flavorumami. He then patented a method of mass-producing a crystalline salt of glutamic acid, monosodium glutamate.[15][16]
Glutamic acid is produced on the largest scale of any amino acid, with an estimated annual production of about 1.5 million tons in 2006.[18] Chemical synthesis was supplanted by theaerobic fermentation of sugars and ammonia in the 1950s, with the organismCorynebacterium glutamicum (also known asBrevibacterium flavum) being the most widely used for production.[19] Isolation and purification can be achieved by concentration andcrystallization; it is also widely available as itshydrochloride salt.[20]
Glutamate is a key compound in cellularmetabolism. In humans, dietaryproteins are broken down by digestion intoamino acids, which serve as metabolic fuel for other functional roles in the body. A key process in amino acid degradation istransamination, in which the amino group of an amino acid is transferred to an α-ketoacid, typically catalysed by atransaminase. The reaction can be generalised as such:
A very common α-keto acid isα-ketoglutarate, an intermediate in thecitric 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:
Glutamate also plays an important role in the body's disposal of excess or wastenitrogen. Glutamate undergoesdeamination, an oxidative reaction catalysed byglutamate dehydrogenase,[17] as follows:
Ammonia (asammonium) is then excreted predominantly asurea, synthesised in theliver. 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.
Glutamate is also aneurotransmitter (see below), which makes it one of the most abundant molecules in the brain. Malignant brain tumors known asglioma orglioblastoma exploit this phenomenon by using glutamate as an energy source, especially when these tumors become more dependent on glutamate due to mutations in the geneIDH1.[21][22]
Extracellular glutamate inDrosophila brains has been found to regulate postsynaptic glutamate receptor clustering, via a process involving receptor desensitization.[26] A gene expressed inglial cells actively transports glutamate into theextracellular space,[26] while, in thenucleus accumbens-stimulating group IImetabotropic glutamate receptors, this gene was found to reduce extracellular glutamate levels.[27] This raises the possibility that this extracellular glutamate plays an "endocrine-like" role as part of a larger homeostatic system.
Stiff person 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 has abundant GAD, a direct immunological destruction occurs in the pancreas and the patients will havediabetes mellitus.[31]
Glutamic acid, being a constituent of protein, is present in foods that contain protein, but it can only be tasted when it is present in an unbound form. Significant amounts of free glutamic acid are present in a wide variety of foods, includingcheeses andsoy sauce, and glutamic acid is responsible forumami, one of the fivebasic tastes of the human sense oftaste. Glutamic acid often is used as afood additive andflavor enhancer in the form of its sodiumsalt, known as monosodium glutamate (MSG).
All meats, poultry, fish, eggs, dairy products, andkombu are excellent sources of glutamic acid. Some protein-rich plant foods also serve as sources. 30% to 35% of gluten (much of the protein in wheat) is glutamic acid. Ninety-five percent of the dietary glutamate is metabolized by intestinal cells in a first pass.[32]
^Webster's Third New International Dictionary of the English Language Unabridged, Third Edition, 1971.
^Robert Sapolsky (2005),Biology and Human Behavior: The Neurological Origins of Individuality (2nd edition);The Teaching Company. pp. 19–20 of the Guide Book.
^Rodante, F.; Marrosu, G. (1989). "Thermodynamics of the second proton dissociation processes of nine α-amino-acids and the third ionization processes of glutamic acid, aspartic acid and tyrosine".Thermochimica Acta.141:297–303.Bibcode:1989TcAc..141..297R.doi:10.1016/0040-6031(89)87065-0.
^Lehmann, Mogens S.; Koetzle, Thomas F.; Hamilton, Walter C. (1972). "Precision neutron diffraction structure determination of protein and nucleic acid components. VIII: the crystal and molecular structure of the β-form of the amino acidl-glutamic acid".Journal of Crystal and Molecular Structure.2 (5):225–233.Bibcode:1972JCCry...2..225L.doi:10.1007/BF01246639.S2CID93590487.
^abcWilliam H. Brown and Lawrence S. Brown (2008),Organic Chemistry (5th edition). Cengage Learning. p. 1041.ISBN0495388572,978-0495388579.
^National Center for Biotechnology Information, "D-glutamate".PubChem Compound Database, CID=23327. Accessed 2017-02-17.
^R. H. A. Plimmer (1912) [1908]. R. H. A. Plimmer; F. G. Hopkins (eds.).The Chemical Constitution of the Protein. Monographs on biochemistry. Vol. Part I. Analysis (2nd ed.). London: Longmans, Green and Co. p. 114. Retrieved3 June 2012.
^McEntee, W. J.; Crook, T. H. (1993). "Glutamate: Its role in learning, memory, and the aging brain".Psychopharmacology.111 (4):391–401.doi:10.1007/BF02253527.PMID7870979.S2CID37400348.
^Zheng Xi; Baker DA; Shen H; Carson DS; Kalivas PW (2002). "Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens".Journal of Pharmacology and Experimental Therapeutics.300 (1):162–171.doi:10.1124/jpet.300.1.162.PMID11752112.
^Coplan JD, Mathew SJ, Smith EL, Trost RC, Scharf BA, Martinez J, Gorman JM, Monn JA, Schoepp DD, Rosenblum LA (July 2001). "Effects of LY354740, a novel glutamatergic metabotropic agonist, on nonhuman primate hypothalamic-pituitary-adrenal axis and noradrenergic function".CNS Spectr.6 (7):607–612, 617.doi:10.1017/S1092852900002157.PMID15573025.S2CID6029856.
^Felizola SJ, Nakamura Y, Satoh F, Morimoto R, Kikuchi K, Nakamura T, Hozawa A, Wang L, Onodera Y, Ise K, McNamara KM, Midorikawa S, Suzuki S, Sasano H (January 2014). "Glutamate receptors and the regulation of steroidogenesis in the human adrenal gland: The metabotropic pathway".Molecular and Cellular Endocrinology.382 (1):170–177.doi:10.1016/j.mce.2013.09.025.PMID24080311.S2CID3357749.
