Glutamic acid

Glutamic acid (abbreviated as Glu or E; Glx or Z represents either glutamic acid or glutamate), is one of the 20 proteinogenic amino acids. It is not among the human essential amino acids. Its codons are GAA and GAG. The carboxylate anion of glutamic acid is known as glutamate.

As its name indicates, glutamic acid has a carboxylic acid component to its side chain. At typical pH's, the amino group is protonated and one or both of the carboxylic groups will be ionized. At neutral pH all three groups are ionized, and the species has a charge of -1. The pK_a value for glutamic acid is 4.1, which means that below this pH, the carboxylic acid groups are not ionized in more than half of the molecules.

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Biosynthesis

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 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-ketoacid 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 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 + NADP⁺ → α-ketoglutarate + NADPH + 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 swift 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 Ca²⁺;^[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 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^[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.

GABA precursor

Glutamic acid 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 at 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.

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 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 instead this transport is mediated by a high affinity transport system ^[1]. It can also be converted into glutamine.

References

In line

1. ^ Transport of glutamate and other amino acids at the blood-brain barrier.Smith QR

Other

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
3. ^a  Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res Brain Res Rev. 2004 Jul; 45(3):250-65. PubMed
4. ^a  Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. Mol Pharmacol. 1989 Jul;36(1):106-12; PubMed
5. ^a  Reeds, P.J., et al. (2000). "Intestinal glutamate metabolism". Journal of Nutrition 130 (4s): 978S-982S. PMID 10736365.. Free text
6.   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
7.   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.
8.   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.