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Glutamate)
Glutamic acid (Glu) or glutamate (the anionic form) is one of the 20 standard amino acids used by all organisms in their proteins. Glu is critical for proper cell function, but it is not an essential nutrient in humans because it can be manufactured from other compounds.
Structure
As its name indicates, it is acidic, with a carboxylic acid component to its side chain.
A three-letter designation for either Gln or Glu is Glx. The one-letter abbreviation is E for glutamic acid and Q for glutamine.
Synthesis
Natural
Commercial
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 ⇌ 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 ⇌ 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.
As a neurotransmitter
Glu is the most abundant excitatory neurotransmitter in the nervous system. In the synaptic cleft glutamic acid binds to two type of receptors: ionotropic and metabotropic glutamic acid receptors. The ionotropic receptors are non-NMDA (AMPA and kainate) and NMDA receptors. 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. Both the pre- and post-synaptic neurons at glutamic acid synapse have glutamic acid-reuptake systems which quickly lower glutamic acid concentration.
In excess, glutamic acid triggers a process called excitotoxicity, causing neuronal damage and eventual cell death, particularly when NMDA receptors are activated. This may be due to:
These theories are based on the observation that epileptic patients often show evidence of neurodegeneration on post-mortem examination.
Glutamate transporters exist in neuronal and glial membranes to remove excess glutamate from the extracellular space, thereby preventing a buildup of glutamate and the damage that such a buildup would cause [3].
Glutamic acid overstimulation occurs as part of the ischemic cascade and is associated with 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. It's been suggested that a fall in resting membrane potential at seizure foci could cause spontaneous opening of VOCCs, leading to glutamic acid release and further depolarisation.
Glutamic acid in action at the synaptic cleft is extremely difficult to study due to its transient nature. A team at Stanford University has developed a nanosensor to detect the release of glutamate by nerve cells. The sensor, constructed of proteins, has a pair of lobes that are hinged like a Venus flytrap. When glutamic acid binds to the proteins, the lobes snap shut. Two fluorescent jellyfish proteins are attached to the sensor. One of these proteins both emits blue light and excites a second protein that emits yellow light. When the lobes snap shut on glutamic acid, the blue protein moves away from the yellow protein, decreasing the glow from the yellow. A dimming of the yellow light indicates that glutamic acid has been released from a nerve cell. The sensor can currently be located only on the surface of cell so it can indicate glutamic acid activity only outside the cell [2].
A special form of glutamic acid can be uncaged using ultraviolet light, delivering glutamic acid to specific parts of a neuron or specific neurons. This method of photostimulation has proven very useful for mapping the connections between neurons.
GABA precursor
Glu also serves as the precursor for the synthesis of the inhibitory GABA in GABA-ergic neurons.
Sources and absorption
Glutamate 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 combination with salt. For this reason, the sodium salt of glutamic acid, monosodium glutamate (MSG) is extensively used as a food additive and general-purpose flavor enhancer.
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. For being so important in the brain functions it is therefore of no surprise that free glutamic acid cannot cross BBB in appreciable quantities; instead it is converted into glutamine.
References
- Nelson DL and Cox MM. Lehninger Principles of Biochemistry, 4th edition.
- a
Okumoto, S., et al. (2005). "Detection of glutamate release from neurons by genetically encoded surface-displayed FRET nanosensors". Proceedings of the National Academy of Sciences U.S.A 102 (24): 8740-8745. PMID 15939876. Free text
- a Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res Brain Res Rev. 2004 Jul; 45(3):250-65. PMID 15210307
- a Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. Mol Pharmacol. 1989 Jul;36(1):106-12; PMID 2568579
External links
The content of this page is retrieved from http://en.wikipedia.org/wiki/Glutamate under GFDL
