Glutamic acid
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Glutamic acid (Glu), also referred to as glutamate (the anion), is one of the 20 proteinogenic amino acids. It is not among the essential amino acids.
Contents |
Structure
As its name indicates, it is acidic, with a carboxylic acid component to its side chain. Generally either the amino group will be protonated or one or both of the carboxylic groups will be deprotonated. At neutral pH all three groups are ionized and the species has a charge of -1.
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.
Synthesis
Natural
| Reaction | 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 |
Function
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 or 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 Template:Unicode R1-α-ketoacid + R2-amino acid
A very common α-ketoacid is α-ketoglutarate, an intermediate in the citric acid cycle. When α-ketoglutarate undergoes transamination, it always results in glutamate being formed as the corresponding amino acid product. 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 Template:Unicode pyruvate + glutamate
- aspartate + α-ketoglutarate Template:Unicode 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:
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.
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 transportersTemplate:Ref N 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+Template:Ref N.
- 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 depolarising 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 nanosensorTemplate:Ref N. 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 describedTemplate:Ref N. This method of rapidly uncaging by photostimulation is useful for mapping the connections between neurons, and understanding synapse function.
GABA precursor
Glu also serves as the precursor for the synthesis of the inhibitory GABA in GABA-ergic neurons.
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 in a neutral pH. Ninety-five percent of the dietary glutamate is metabolized by intestinal cells in a first pass Template:Ref N.
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.
Pharmacology
The drug phencyclidine (more commonly known as PCP) antagonizes glutamic acid non-competitively at the NMDA receptor, causing behavior reminiscent of schizophrenia. For the same reasons, sub-anaesthetic doses of Ketamine have strong dissociative and hallucinogenic effects. Glutamate easily passes the blood brain barrier: "glutamate flux from plasma into brain is mediated by a high affinity transport system at the BBB" [1]. It can also be converted into glutamine, also a reversible reaction.
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. No similar diets for schizophrenia are known.
References
- Nelson DL and Cox MM. Lehninger Principles of Biochemistry, 4th edition.
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|[{{{url}}} Detection of glutamate release from neurons by genetically encoded surface-displayed FRET nanosensors]
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|[{{{url}}} Postsynaptic activation at the squid giant synapse by photolytic release of L-glutamate from a 'caged' L-glutamate]
|Postsynaptic activation at the squid giant synapse by photolytic release of L-glutamate from a 'caged' L-glutamate
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External links
- Links to external chemical sources{{#if:|:* ChemQuik search for CAS {{{cas}}}: [2]}}{{#if:|{{#if:|:* ChemQuik search for name "{{{name}}}": [3]}}}}
