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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 memory.
Chemistry
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
Glutamic acid (flavour)
Although they occur naturally in many foods, the flavour 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 Leopold Ritthausen who treated wheat
gluten (for which it was named) with sulfuric acid. 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 flavour he detected in many foods, most especially in seaweed.
Professor Ikeda termed this flavour umami. He then patented a method of mass-producing
a crystalline salt of glutamic acid, monosodium glutamate.
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-keto acid transaminase
1-Pyrroline-5-carboxylate + ***+ + H2O → Glu + NADH ALDH4A1
N-formimino-L-glutamate + FH4 → Glu + 5-formimino-FH4 FTCD
NAAG → Glu + NAA GCPII
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:
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, 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
Glutamate is the most abundant excitatory neurotransmitter in the vertebrate
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,
glutamate is involved in cognitive functions like learning and memory in the
brain. 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.
Glutamate transporters 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+
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 and diseases like
amyotrophic lateral sclerosis, lathyrism, autism, some forms of mental
retardation, and Alzheimer's disease. In contrast, decreased glutamate
release is observed under conditions of classical phenylketonuria leading to
developmental disruption of glutamate receptor expression.
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. 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. 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. The beta subunits of the receptor respond
with very high affinity to glutamate and glycine. 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. These receptors have also been described in arthropods, such
as Drosophila melanogaster and Lepeophtheirus salmonis. 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.
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. A gene expressed in glial cells actively transports
glutamate into the extracellular space, while, in the nucleus accumbens-stimulating
group II metabotropic glutamate receptors, this gene was found to reduce
extracellular glutamate levels. This raises the possibility that this
extracellular glutamate plays an "endocrine-like" role as part of a larger
homeostatic system.
GABA precursor
Glutamate also serves as the precursor for the synthesis of the inhibitory 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 is also abundant for the
enzyme GAD, a direct immunological destruction occurs in the pancreas and the
patients will have diabetes mellitus.
Flavor enhancer
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 flavour enhancer in the form of its 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 the protein in wheat is glutamic acid. Ninety-five percent of the dietary
glutamate is metabolized by intestinal cells in a first pass.
Plant growth
Auxigro is a plant growth preparation that contains 30% glutamic acid.
NMR spectroscopy
In recent years, there has been much research into the use of RDCs in NMR
spectroscopy. 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.
Production
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
The drug phencyclidine (more commonly known as ***) 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. Glutamate does not easily pass the blood brain barrier,
but, instead, is transported by a high-affinity transport system. It can
also be converted into glutamine.