Glutamic acid

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Glutamic acid
Systematic (IUPAC) name
(2S)-2-aminopentanedioic acid
Identifiers
PubChem	?
Chemical data
Formula	C5H9NO4
Mol. weight	147.13
Complete data

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.

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. The pKa value for Glutamic acid is 4.1. This means that at pH below this value it will be protonated (COOH) and at pH above this value it will be deprotonated (COO-)

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 ⇌ 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

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 Ca^2+[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 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 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.

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.

Link with schizophrenia

Interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in schizophrenia. This has largely been suggested by abnormally low levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia and the discovery that the glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition. The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia. Further support of this theory has come from preliminary trials suggesting the efficacy of coagonists at the NMDA receptor complex in reducing some of the positive symptoms of schizophrenia.

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.

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 ^[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. Although there have been associated complication in the excess consumption of such products.

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: "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.

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.

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Key texts

Papers

1. Nelson DL and Cox MM. Lehninger Principles of Biochemistry, 4th edition.
2. ^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

1. ^a 

Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res Brain Res Rev. 2004 Jul; 45(3):250-65. PMID 15210307

1. ^a 

Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. Mol Pharmacol. 1989 Jul;36(1):106-12; PMID 2568579

1. ^a 

 Reeds, P.J., et al. (2000).  Intestinal glutamate metabolism. Journal of Nutrition 130 (4s): 978S-982S. PMID 10736365.. Free text

1.  

 Corrie, J.E., et al. (1993).  Postsynaptic activation at the squid giant synapse by photolytic release of L-glutamate from a 'caged' L-glutamate. Journal of Physiology 465 (Jun): 1-8. PMID 7901400. Free text 

1.  

Augustin H, Grosjean Y, Chen K, Sheng Q, Featherstone DE (2007).  Nonvesicular release of glutamate by glial xCT transporters suppresses glutamate receptor clustering in vivo. Journal of Neuroscience 27 (1): 111-123. PMID 17202478.

1.  

Zheng Xi, Baker DA, Shen H, Carson DS, Kalivas PW (2002).  Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens. Journal of Pharmacology and Experimental Therapeutics 300 (1): 162-171. PMID 11752112.

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