Glutamic acid

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Glutamic acid (Gloo-tah-mih-k)
Skeletal formula of glutamic acid
Ball-and-stick model of the zwitterion
Identifiers
CAS number 617-65-2 YesY
ChemSpider 591 YesY
UNII 61LJO5I15S YesY
KEGG D0434 YesY
ChEBI CHEBI:18237 YesY
ChEMBL CHEMBL276389. YesY
Jmol-3D images Image 1
Properties
Molecular formula C5H9NO4
Molar mass 147.13 g mol−1
Appearance white crystalline powder
Density 1.4601 (20 °C)
Melting point 199 °C decomp.
Solubility in water 8.64 g/l (25 °C) [1]
Solubility 0.00035g/100g ethanol 25 degC [2]
Acidity (pKa) 2.1, 4.07, 9.47 [3]
Hazards
MSDS External MSDS
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroform Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
Supplementary data page
Structure and
properties
n, εr, etc.
Thermodynamic
data
Phase behaviour
Solid, liquid, gas
Spectral data UV, IR, NMR, MS
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 YesY (verify) (what is: YesY/N?)
Infobox references

Glutamic acid (abbreviated as Glu or E) is one of the 20-22 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates. In neuroscience, glutamate is an important neurotransmitter that plays a key role in long-term potentiation and is important for learning and retaining memory.[4]

Chemistry[edit]

The side chain carboxylic acid functional group has a pKa of 4.1 and therefore exists almost entirely in its negatively charged deprotonated carboxylate form at pH values greater than 4.1; therefore, it is negatively charged at physiological pH ranging from 7.35 to 7.45.

History[edit]

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 Ritthausen who treated wheat gluten (for which it was named) with sulfuric acid.[5] 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.[6][7]

Biosynthesis[edit]

Reactants Products Enzymes
Glutamine + H2O Glu + NH3 GLS, GLS2
NAcGlu + H2O Glu + Acetate N-acetyl-glutamate synthase
α-ketoglutarate + NADPH + NH4+ Glu + NADP+ + H2O GLUD1, GLUD2[8]
α-ketoglutarate + α-amino acid Glu + α-keto acid transaminase
1-Pyrroline-5-carboxylate + NAD+ + H2O Glu + NADH ALDH4A1
N-formimino-L-glutamate + FH4 Glu + 5-formimino-FH4 FTCD
NAAG Glu + NAA GCPII


Function and uses[edit]

Metabolism[edit]

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:

R1-amino acid + R2-α-ketoacid R1-α-ketoacid + R2-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 pyruvate + glutamate
Aspartate + α-ketoglutarate 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,[8] as follows:

glutamate + H2O + NADP+ → α-ketoglutarate + NADPH + NH3 + H+

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[edit]

Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system.[9] At 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 or the AMPA 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.[10] 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.[11] In addition, glutamate plays important roles in the regulation of growth cones and synaptogenesis during brain development as originally described by Mark Mattson.

Glutamate transporters[12] are found in neuronal and glial 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 cell death include

  • Glu/Ca2+-mediated promotion of transcription factors for pro-apoptotic genes, or downregulation of transcription factors for anti-apoptotic genes

Excitotoxicity due to excessive glutamate release and impaired uptake occurs as part of the ischemic cascade and is associated with stroke,[4] autism, some forms of intellectual disability, and diseases like amyotrophic lateral sclerosis, lathyrism, and Alzheimer's disease.[4][14] In contrast, decreased glutamate release is observed under conditions of classical phenylketonuria[15] leading to developmental disruption of glutamate receptor expression.[16]

Glutamic acid has been implicated in epileptic seizures. Microinjection of glutamic acid into neurons produces spontaneous depolarisations 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 voltage-activated calcium channels, leading to glutamic acid release and further depolarization[citation needed].

Experimental techniques to detect glutamate in intact cells include using a genetically engineered nanosensor.[17] 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 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.[18] 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.[citation needed] The beta subunits of the receptor respond with very high affinity to glutamate and glycine.[19] Targeting these receptors has been the therapeutic goal of anthelmintic therapy using avermectins. Avermectins target the alpha-subunit of glutamate-gated chloride channels with high affinity.[20] These receptors have also been described in arthropods, such as Drosophila melanogaster[21] and Lepeophtheirus salmonis.[22] 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.

L-Glutamate at physiological conditions

Brain nonsynaptic glutamatergic signaling circuits[edit]

Extracellular glutamate in Drosophila brains has been found to regulate postsynaptic glutamate receptor clustering, via a process involving receptor desensitization.[23] A gene expressed in glial cells actively transports glutamate into the extracellular space,[23] while, in the nucleus accumbens-stimulating group II metabotropic glutamate receptors, this gene was found to reduce extracellular glutamate levels.[24] This raises the possibility that this extracellular glutamate plays an "endocrine-like" role as part of a larger homeostatic system.

GABA precursor[edit]

Glutamate also serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (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 has abundant GAD, a direct immunological destruction occurs in the pancreas and the patients will have diabetes mellitus.

Flavor enhancer[edit]

Glutamic acid, being a constituent of protein, is present in every food that contains 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 cheese and soy sauce, and is responsible for umami, one of the five basic tastes of the human sense of taste. Glutamic acid is often used as a food additive and flavor enhancer in the form of its salt, known as monosodium glutamate (MSG).

Nutrient[edit]

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 the protein in wheat is glutamic acid. Ninety-five percent of the dietary glutamate is metabolized by intestinal cells in a first pass.[25]

Plant growth[edit]

Auxigro is a plant growth preparation that contains 30% glutamic acid.

NMR spectroscopy[edit]

In recent years, 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.[26]

Production[edit]

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%–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[edit]

The drug phencyclidine (more commonly known as PCP) antagonizes glutamic acid non-competitively at the NMDA receptor. For the same reasons, dextromethorphan and ketamine also have strong dissociative and hallucinogenic effects. Acute infusion of the drug LY354740 (also known as eglumegad, an agonist of the metabotropic glutamate receptors 2 and 3) resulted in a marked diminution of yohimbine-induced stress response in bonnet macaques (Macaca radiata); chronic oral administration of LY354740 in those animals led to markedly reduced baseline cortisol levels (approximately 50 percent) in comparison to untreated control subjects.[27] LY354740 has also been demonstrated to act on the metabotropic glutamate receptor 3 (GRM3) of human adrenocortical cells, downregulating aldosterone synthase, CYP11B1, and the production of adrenal steroids (i.e. aldosterone and cortisol).[28] Glutamate does not easily pass the blood brain barrier, but, instead, is transported by a high-affinity transport system.[29] It can also be converted into glutamine.

See also[edit]

References[edit]

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  13. ^ Hynd, M.; Scott, H. L.; Dodd, P. R. (2004). "Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer?s disease". Neurochemistry International 45 (5): 583–595. doi:10.1016/j.neuint.2004.03.007. PMID 15234100.  edit
  14. ^ Glushakov, AV; Dennis, DM; Sumners, C; Seubert, CN; Martynyuk, AE (Apr 1, 2003). "L-phenylalanine selectively depresses currents at glutamatergic excitatory synapses". Journal of neuroscience research 72 (1): 116–24. doi:10.1002/jnr.10569. PMID 12645085. 
  15. ^ Glushakov, AV; Glushakova, O; Varshney, M; Bajpai, LK; Sumners, C; Laipis, PJ; Embury, JE; Baker, SP; Otero, DH; Dennis, DM; Seubert, CN; Martynyuk, AE (February 2005). "Long-term changes in glutamatergic synaptic transmission in phenylketonuria". Brain : a journal of neurology 128 (Pt 2): 300–7. doi:10.1093/brain/awh354. PMID 15634735. 
  16. ^ Okumoto, S.; Looger, L. L.; Micheva, K. D.; Reimer, R. J.; Smith, S. J.; Frommer, W. B. (2005). "Detection of glutamate release from neurons by genetically encoded surface-displayed FRET nanosensors". Proceedings of the National Academy of Sciences 102 (24): 8740. doi:10.1073/pnas.0503274102.  edit
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  26. ^ 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): 607–12, 617. PMID 15573025. 
  27. ^ Felizola SJA, 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. PMID 24080311. 
  28. ^ Smith QR (April 2000). "Transport of glutamate and other amino acids at the blood–brain barrier". J. Nutr. 130 (4S Suppl): 1016S–22S. PMID 10736373. 

External links[edit]

Further reading[edit]

  • Nelson, David L.; Cox, Michael M. (2005), Principles of Biochemistry (4th ed.), New York: W. H. Freeman, ISBN 0-7167-4339-6