Glutamic acid
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| Glutamic acid | |
| Systematic (IUPAC) name | |
| (2S)-2-aminopentanedioic acid | |
| Identifiers | |
| CAS number | 56-86-0 |
| PubChem | 611 |
| Chemical data | |
| Formula | C5H9NO4 |
| Molar mass | 147.13 g/mol |
| SMILES | N[C@@H](CCC(O)=O)C(O)=O |
| Complete data | |
Glutamic acid (Glu, E), is the protonated form of glutamate (the anion). Glutamate is one of the 20 proteinogenic amino acids. It is not among the essential amino acids. A three-letter designation for either Gln or Glu is Glx—this is often used in cases in which peptide sequencing reactions may convert glutamine to glutamate (or vice versa), leaving the original identity of the amino acid in doubt. The one-letter abbreviation is E for glutamic acid and Q for glutamine.
As its name indicates, glutamic acid has a carboxylic acid component to its side chain. At typical pH's, the amino group is protonated and one or both of the carboxylic groups will be ionized. At neutral pH all three groups are ionized, and the species has a charge of -1. The pKa value for glutamic acid is 4.1, which means that below this pH, the carboxylic acid groups are not ionized in more than half of the molecules.
Contents
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[edit] Biosynthesis
| Reactants | Products | Enzymes |
|---|---|---|
| Glutamine + H2O | → Glu + NH3 | GLS, GLS2 |
| NAcGlu + H2O | → Glu + Acetate | (unknown) |
| α-ketoglutarate + NADPH + NH4+ | → Glu + NADP+ + H2O | GLUD1, GLUD2 |
| α-ketoglutarate + α-amino acid | → Glu + α-oxo acid | transaminase |
| 1-pyrroline-5-carboxylate + NAD+ + H2O | → Glu + NADH | ALDH4A1 |
| N-formimino-L-glutamate + FH4 | → Glu + 5-formimino-FH4 | FTCD |
[edit] Function
[edit] In metabolism
Glutamate is a key molecule in cellular metabolism. In humans, dietary proteins are broken down by digestion into amino acids, which serves 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-ketoacid 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 also 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 + water + NAD+ → α-ketoglutarate + NADH + ammonia + 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.
[edit] As a neurotransmitter
Glutamate is the most abundant fast excitatory neurotransmitter in the mammalian nervous system. 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, bind glutamate and are activated. Because of its role in synaptic plasticity, it is believed that glutamic acid is involved in cognitive functions like learning and memory in the brain.
Glutamate transporters[3] 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:
- Damage to mitochondria from excessively high intracellular Ca2+[4].
- Glu/Ca2+-mediated promotion of transcription factors 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 and diseases like amyotrophic lateral sclerosis, lathyrism, and Alzheimer's disease.
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.
Experimental techniques to detect glutamate in intact cells include using a genetically-engineered nanosensor[2]. 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 have also been described[6]. This method of rapidly uncaging by photostimulation is useful for mapping the connections between neurons, and understanding synapse function.
[edit] In 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[7]. A gene expressed in glial cells actively transports glutamate into the extracellular space[7], while in the nucleus accumbens stimulating group II metabotropic glutamate receptors was found to reduce extracellular glutamate levels[8]. This raises the possibility that this extracellular glutamate plays an "endocrine-like" role as part of a larger homeostatic system.
[edit] GABA precursor
Glu also serves as the precursor for the synthesis of the inhibitory GABA in GABA-ergic neurons. This reaction is catalyzed by GAD, glutamic acid decarboxylase, which is most abundant in 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.
[edit] Sources and absorption
Glutamic acid is present in a wide variety of foods and is responsible for one of the five basic tastes of the human sense of taste (umami), especially in its physiological form, the sodium salt of glutamate at neutral pH. Ninety-five percent of the dietary glutamate is metabolized by intestinal cells in a first pass [5].
Overall, glutamic acid is the single largest contributor to intestinal energy. As a source for umami, the sodium salt of glutamic acid, monosodium glutamate (MSG) is used as a food additive to enhance the flavor of foods, although an identical effect can be achieved by mixing and cooking together different ingredients rich in this amino acid and other umami substances as well.
Another source of MSG is fruits, vegetables and nuts that have been sprayed with Auxigro. Auxigro is a growth enhancer that contains 30% glutamic acid.
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.
[edit] Pharmacology
The drug phencyclidine (more commonly known as PCP) 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 this transport is mediated by a high affinity transport system [1]. It can also be converted into glutamine.
Glutamate transport and supply are obvious targets for the treatment of epilepsy, therefore. In particular Glutamate Restriction Diets are now claiming success anecdotally, by limiting or eliminating intake of wheat, peanut, soy and bean.
High glutamate diets, that is, with brewer's yeast, have also been successful in treating schizophrenia. There is, however, no published data to this effect.