Glutamic acid

Glutamic acid
Chemical name	(S)-2-Aminopentanedioic acid
Abbreviations	Glu E
Chemical formula	C5H9NO4
Molecular mass	147.13 g mol-1
Melting point	247-249 °C
Density	1.538 g/cm3
Isoelectric point	3.22
pKa	2.16 4.15 9.58
CAS number	[56-86-0]
EINECS number	200-293-7
SMILES	OC(=O)CCC(N)C(=O)O

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

Reaction	Enzymes
Glutamine + H2O --> Glu + NH4+	GLS, GLS2
NAcGlu + H2O --> Glu + Acetate	(unknown)
Ketoglutaric acid + NADPH + NH4+ --> Glu + NADP+ + H2O	GLUD1, GLUD2
Ketoglutaric acid + 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 in the diet 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 neurotransmiter

Glu is the most abundant excitatory neurotransmitter in the nervous system. In the synaptic cleft Glu binds to two type of receptors ionotropic and metabotropic Glu receptors. The ionotropic receptors are non-NMDA (AMPA and kainate) and NMDA receptors. Because of its role in synaptic plasticity, it is believed that Glu is involved in cognitive functions like learning and memory in the brain. Both the pre- and post-synaptic neurons at Glu synapse have Glu-reuptake systems which quickly lower Glu concentration.

In excess, Glu triggers a process called excitotoxicity, causing neuronal damage and eventual cell death, particularly when NMDA receptors are activated. This may be due to:

• High intracellular Ca²⁺ exceeding storage capacity [1] and damaging mitochondria, leading to release of cytochrome C and apoptosis.
• Glu/Ca²⁺-mediated promotion of transcription factors for pro-apoptotic genes, or downregulation of transcription factors for anti-apoptotic genes.

These theories are based on the observation that epileptic patients often show evidence of neurodegeneration on post-mortem examination.

Glu overstimulation occurs in ishemia. Glu induced neuronal damage is also associated with diseases like amyotrophic lateral sclerosis, lathyrism, and Alzheimer's disease.

Glu has been implicated in epileptic seizures. Microinjection of Glu 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 Glu release and further depolarisation.

Glu 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 Glu 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 Glu, the blue protein moves away from the yellow protein, decreasing the glow from the yellow. A dimming of the yellow light indicates that Glu has been released from a nerve cell. The sensor can currently be located only on the surface of cell so it can indicate Glu activity only outside the cell (Okumoto, et al., 2005).

A special form of Glu can be uncaged using ultraviolet light, delivering Glu 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 absorbtion

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 Glu, 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 Glu 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 Glu cannot cross BBB in appreciable quantities; instead it is converted into Glu.

References

• Template:Journal reference issue PMID 15939876

External link

• More on MSG as a food additive