Glutamic acid (symbol Glu or E;[4] the anionic form is known as glutamate) 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 GABAergic neurons.
Its molecular formula is C 5H 9NO 4. Glutamic acid exists in two optically isomeric forms; the dextrorotatory L-form is usually obtained by hydrolysis of gluten or from the waste waters of beet-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 two carboxyl groups −COOH and one amino group −NH 2. However, in the solid state and mildly acidic water solutions, the molecule assumes an electrically neutralzwitterion structure −OOC−CH(NH+ 3)−(CH 2)2−COOH. It is encoded by the codons GAA or GAG.
The acid can lose one proton from its second carboxyl group to form the conjugate base, the singly-negative anionglutamate−OOC−CH(NH+ 3)−(CH 2)2−COO−. This form of the compound is prevalent in neutral solutions. The glutamate neurotransmitter plays the principal role in neural activation.[6] This anion creates the savory umami flavor of foods and is found in glutamate flavorings such as MSG. In Europe, it is classified as food additive E620. In highly alkaline solutions the doubly negative anion −OOC−CH(NH 2)−(CH 2)2−COO− prevails. The radical corresponding to glutamate is called glutamyl.
The one-letter symbol E for glutamate was assigned in alphabatical sequence to D for aspartate, being larger by one methylene –CH2– group.[7]
Chemistry
Ionization
The glutamate monoanion.
When glutamic acid is dissolved in water, the amino group (−NH 2) may gain a proton (H+ ), and/or the carboxyl groups may lose protons, depending on the acidity of the medium.
In sufficiently acidic environments, both carboxyl groups are protonated and the molecule becomes a cation with a single positive charge, HOOC−CH(NH+ 3)−(CH 2)2−COOH.[8]
At pH 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 the physiological 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 chemist Karl Heinrich Ritthausen, who treated wheat gluten (for which it was named) with sulfuric acid.[14] In 1908, 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.[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 the aerobic fermentation of sugars and ammonia in the 1950s, with the organism Corynebacterium glutamicum (also known as Brevibacterium flavum) being the most widely used for production.[19] Isolation and purification can be achieved by concentration and crystallization; it is also widely available as its hydrochloride salt.[20]
Function and uses
Metabolism
Glutamate is a key compound 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:
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:
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,[17] as follows:
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.
Glutamate is also a neurotransmitter (see below), which makes it one of the most abundant molecules in the brain. Malignant brain tumors known as glioma or glioblastoma exploit this phenomenon by using glutamate as an energy source, especially when these tumors become more dependent on glutamate due to mutations in the gene IDH1.[21][22]
Extracellular glutamate in Drosophila brains has been found to regulate postsynaptic glutamate receptor clustering, via a process involving receptor desensitization.[26] A gene expressed in glial cells actively transports glutamate into the extracellular space,[26] while, in the nucleus accumbens-stimulating group II metabotropic 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 have diabetes 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, including cheeses and soy sauce, and glutamic acid is responsible for umami, one of the five basic tastes of the human sense of taste. Glutamic acid often is used as a food additive and flavor enhancer in the form of its sodium salt, known as monosodium glutamate (MSG).
Nutrient
All meats, poultry, fish, eggs, dairy products, and kombu 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]
Plant growth
Auxigro is a plant growth preparation that contains 30% glutamic acid.
NMR spectroscopy
In recent years,[when?] there has been much research into the use of residual dipolar coupling (RDC) in nuclear magnetic resonance spectroscopy (NMR). A glutamic acid derivative, poly-γ-benzyl-L-glutamate (PBLG), is often used as an alignment medium to control the scale of the dipolar interactions observed.[33]
^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.
^ abAlbert Neuberger (1936), "Dissociation constants and structures of glutamic acid and its esters". Biochemical Journal, volume 30, issue 11, article CCXCIII, pp. 2085–2094. PMC1263308.
^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. 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. 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. Retrieved 3 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.
^C. M. Thiele, Concepts Magn. Reson. A, 2007, 30A, 65–80
^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.
