Glutamic acid
Encyclopedia
Glutamic acid is one of the 20 proteinogenic amino acid
s, and its codons are GAA and GAG. It is a non-essential amino acid
. The carboxylate anion
s 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.
carboxylic acid
functional group
has pKa
of 4.1 and exists in its negatively charged deprotonated
carboxylate form at physiological pH ranging from 7.35 to 7.45.
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 flavor he detected in many foods, most especially in seaweed. Professor Ikeda termed this flavor umami
. He then patented a method of mass-producing a crystalline salt of glutamic acid, monosodium glutamate
.
. 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:
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:
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:
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.
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 transporter
s are found in neuron
al 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
Excitotoxicity due to glutamate 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
.
Glutamic acid has been implicated in epileptic seizure
s. 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 avermectin
s. 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.
brains has been found to regulate postsynaptic glutamate receptor clustering, via a process involving receptor desensitization. A gene expressed in glial cell
s 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.
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.
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 sodium
salt
monosodium glutamate
(MSG).
are excellent sources of glutamic acid. Some protein-rich plant foods also serve as sources. Thirty 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.
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.
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.
(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, is transported by a high-affinity transport system. It can also be converted into glutamine
.
Proteinogenic amino acid
Proteinogenic amino acids are those amino acids that can be found in proteins and require cellular machinery coded for in the genetic code of any organism for their isolated production. There are 22 standard amino acids, but only 21 are found in eukaryotes. Of the 22, 20 are directly encoded by...
s, and its codons are GAA and GAG. It is a non-essential amino acid
Essential amino acid
An essential amino acid or indispensable amino acid is an amino acid that cannot be synthesized de novo by the organism , and therefore must be supplied in the diet.-Essentiality vs. conditional essentiality in humans:...
. The carboxylate anion
Carboxylate anion
A carboxylate is a salt or ester of a carboxylic acid.Carboxylate salts have the general formula Mn, where M is a metal and n is 1,2,...; carboxylate esters have the general formula RCOOR'. R and R' are organic groups; R'≠H....
s and salts of glutamic acid are known as glutamates. In neuroscience
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...
, glutamate is an important neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
that plays a key role in long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
and is important for learning and memory.
Chemistry
The side chainSide chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...
carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
functional group
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
has pKa
Acid dissociation constant
An acid dissociation constant, Ka, is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions...
of 4.1 and exists in its negatively charged deprotonated
Deprotonation
Deprotonation is the removal of a proton from a molecule, forming the conjugate base.The relative ability of a molecule to give up a proton is measured by its pKa value. A low pKa value indicates that the compound is acidic and will easily give up its proton to a base...
carboxylate form at physiological pH ranging from 7.35 to 7.45.
History
Although they occur naturally in many foods, the flavor 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. In 1907 Japanese researcher Kikunae IkedaKikunae Ikeda
was a Japanese chemist and Tokyo Imperial University professor in Chemistry who, in 1908, uncovered the chemical root behind a taste he named umami. He discovered the common component that produced the flavor of meat, seaweed and tomatoes was glutamate, which produces the sensation of umami.He also...
of the Tokyo Imperial University identified brown crystals left behind after the evaporation of a large amount of kombu
Kombu
Kombu or konbu , also called dashima or haidai , is edible kelp from the family Laminariaceae widely eaten in East Asia....
broth as glutamic acid. These crystals, when tasted, reproduced the ineffable but undeniable flavor he detected in many foods, most especially in seaweed. Professor Ikeda termed this flavor umami
Umami
Umami , popularly referred to as savoriness, is one of the five basic tastes together with sweet, sour, bitter, and salty.-Etymology:Umami is a loanword from the Japanese meaning "pleasant savory taste". This particular writing was chosen by Professor Kikunae Ikeda from umai "delicious" and mi ...
. He then patented a method of mass-producing a crystalline salt of glutamic acid, monosodium glutamate
Monosodium glutamate
Monosodium glutamate, also known as sodium glutamate or MSG, is the sodium salt of glutamic acid, one of the most abundant naturally occurring non-essential amino acids....
.
Biosynthesis
| Reactants | Product Product (chemistry) Product are formed during chemical reactions as reagents are consumed. Products have lower energy than the reagents and are produced during the reaction according to the second law of thermodynamics. The released energy comes from changes in chemical bonds between atoms in reagent molecules and... s |
Enzymes |
|---|---|---|
| Glutamine Glutamine Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders... + H2O Water Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a... |
→ Glu + NH3 Ammonia Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or... |
GLS, GLS2 |
| NAcGlu + H2O Water Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a... |
→ Glu + Acetate Acetate An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In... |
(unknown) |
| α-ketoglutarate + NADPH + NH4+ | → Glu + NADP+ + H2O | GLUD1, GLUD2 |
| α-ketoglutarate + α-amino acid Amino acid Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen... |
→ Glu + α-keto acid Keto acid Keto acids are organic compounds that contain a carboxylic acid group and a ketone group. The alpha-keto acids are especially important in biology as they are involved in the Krebs citric acid cycle and in glycolysis... |
transaminase Transaminase In biochemistry, a transaminase or an aminotransferase is an enzyme that catalyzes a type of reaction between an amino acid and an α-keto acid. To be specific, this reaction involves removing the amino group from the amino acid, leaving behind an α-keto acid, and transferring it to the... |
| 1-Pyrroline-5-carboxylate + NAD+ Nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved... + H2O |
→ Glu + NADH | ALDH4A1 |
| N-formimino-L-glutamate + FH4 Folic acid Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9... |
→ Glu + 5-formimino-FH4 Folic acid Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9... |
FTCD |
Metabolism
Glutamate is a key molecule in cellular metabolismMetabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
. 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
Transamination
There are two chemical reactions known as transamination . The first is the reaction between an amino acid and an alpha-keto acid...
, in which the amino group of an amino acid is transferred to an α-ketoacid, typically catalysed by a transaminase
Transaminase
In biochemistry, a transaminase or an aminotransferase is an enzyme that catalyzes a type of reaction between an amino acid and an α-keto acid. To be specific, this reaction involves removing the amino group from the amino acid, leaving behind an α-keto acid, and transferring it to the...
. 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
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
. 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:
- AlanineAlanineAlanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
+ 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
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
, gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
, and the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
.
Glutamate also plays an important role in the body's disposal of excess or waste nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
. Glutamate undergoes deamination
Deamination
Deamination is the removal of an amine group from a molecule. Enzymes which catalyse this reaction are called deaminases.In the human body, deamination takes place primarily in the liver, however glutamate is also deaminated in the kidneys. Deamination is the process by which amino acids are...
, an oxidative reaction catalysed by glutamate dehydrogenase
Glutamate dehydrogenase
Glutamate dehydrogenase is an enzyme, present in most microbes and the mitochondria of eukaryotes, as are some of the other enzymes required for urea synthesis, that converts glutamate to α-Ketoglutarate, and vice versa. In animals, the produced ammonia is, however, usually bled off to the urea...
, as follows:
- glutamate + H2O + NADPNicotinamide adenine dinucleotide phosphateNicotinamide adenine dinucleotide phosphate, abbreviated NADP or TPN in older notation , is a coenzyme used in anabolic reactions, such as lipid and nucleic acid synthesis, which require NADPH as a reducing agent....
+ → α-ketoglutarate + NADPHNicotinamide adenine dinucleotide phosphateNicotinamide adenine dinucleotide phosphate, abbreviated NADP or TPN in older notation , is a coenzyme used in anabolic reactions, such as lipid and nucleic acid synthesis, which require NADPH as a reducing agent....
+ NH3 + H+
Ammonia (as ammonium
Ammonium
The ammonium cation is a positively charged polyatomic cation with the chemical formula NH. It is formed by the protonation of ammonia...
) is then excreted predominantly as urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
, synthesised in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. 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 neurotransmitterNeurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in the vertebrate nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. 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
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
, bind glutamate and are activated. Because of its role in synaptic plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
, glutamate is involved in cognitive functions like learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
in the brain. The form of plasticity known as long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
takes place at glutamatergic synapses in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, neocortex
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
, 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 transporter
Glutamate transporter
Excitatory amino-acid transporters , formerly known as Glutamate transporters, belong to the family of neurotransmitter transporters. They serve to terminate the excitatory neurotransmitter signal by removal of glutamate from the neuronal synapse into Glia cells.In details, the EAATs are...
s are found in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
al and glial membranes. They rapidly remove glutamate from the extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
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
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
channels, leading to neuronal damage and eventual cell death, and is called excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
. The mechanisms of cell death
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
include
- Damage to mitochondria from excessively high intracellular Ca2+CalciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
- Glu/Ca2+-mediated promotion of transcription factorTranscription factorIn molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s for pro-apoptotic genes, or downregulation of transcription factors for anti-apoptotic genes
Excitotoxicity due to glutamate occurs as part of the ischemic cascade
Ischemic cascade
The ischemic cascade is a series of biochemical reactions that are initiated in the brain and other aerobic tissues after seconds to minutes of ischemia . This is typically secondary to stroke, injury, or cardiac arrest due to heart attack. Most ischemic neurons that die do so due to the...
and is associated with stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
and diseases like amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
, lathyrism
Lathyrism
Lathyrism or Neurolathyrism is a neurological disease of humans and domestic animals, caused by eating certain legumes of the genus Lathyrus...
, autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
, some forms of mental retardation, and Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
Glutamic acid has been implicated in epileptic seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s. Microinjection of glutamic acid into neurons produces spontaneous depolarisations around one second
Second
The second is a unit of measurement of time, and is the International System of Units base unit of time. It may be measured using a clock....
apart, and this firing pattern is similar to what is known as paroxysmal depolarizing shift
Paroxysmal depolarizing shift
A paroxysmal depolarizing shift is a cellular manifestation of epilepsy. First, there is a Ca++ mediated depolarization, which causes voltage gated Na+ to open, resulting in action potentials...
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
Nanosensor
Nanosensors are any biological, chemical, or surgical sensory points used to convey information about nanoparticles to the macroscopic world. Their use mainly include various medicinal purposes and as gateways to building other nanoproducts, such as computer chips that work at the nanoscale and...
. The sensor is a fusion of a glutamate-binding protein and two fluorescent proteins. When glutamate binds, the fluorescence of the sensor under ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
light changes by resonance between the two fluorophores
Fluorescence resonance energy transfer
Förster resonance energy transfer , also known as fluorescence resonance energy transfer, resonance energy transfer or electronic energy transfer , is a mechanism describing energy transfer between two chromophores.A donor chromophore, initially in its electronic excited state, may transfer energy...
. Introduction of the nanosensor into cells enables optical detection of the glutamate concentration. Synthetic analogs of glutamic acid that can be activated by ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
light and two-photon excitation microscopy
Two-photon excitation microscopy
Two-photon excitation microscopy is a fluorescence imaging technique that allows imaging of living tissue up to a very high depth, that is up to about one millimeter. Being a special variant of the multiphoton fluorescence microscope, it uses red-shifted excitation light which can also excite...
have also been described. This method of rapidly uncaging by photostimulation
Photostimulation
Photostimulation is the use of light to artificially activate biological compounds, cells, or even whole organisms. Photostimulation can be used to noninvasively probe the causal relationships between different biological processes, using only light...
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
Anthelmintic
Anthelmintics or antihelminthics are drugs that expel parasitic worms from the body, by either stunning or killing them. They may also be called vermifuges or vermicides .-Pharmaceutical classes:...
therapy using avermectin
Avermectin
The avermectins are a series 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties. These naturally occurring compounds are generated as fermentation products by Streptomyces avermitilis, a soil actinomycete...
s. 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 DrosophilaDrosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
brains has been found to regulate postsynaptic glutamate receptor clustering, via a process involving receptor desensitization. A gene expressed in glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s actively transports glutamate into the extracellular space, while, in the nucleus accumbens
Nucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...
-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 GABAGabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
in GABA-ergic neurons. This reaction is catalyzed by glutamate decarboxylase
Glutamate decarboxylase
Glutamate decarboxylase or glutamic acid decarboxylase is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2. GAD uses PLP as a cofactor. The reaction proceeds as follows:...
(GAD), which is most abundant in the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
and pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
.
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 amount of free glutamic acid are present in a wide variety of foods, including cheeseCheese
Cheese is a generic term for a diverse group of milk-based food products. Cheese is produced throughout the world in wide-ranging flavors, textures, and forms....
and soy sauce
Soy sauce
Soy sauce is a condiment produced by fermenting soybeans with Aspergillus oryzae or Aspergillus sojae molds, along with water and salt...
, and is responsible for umami
Umami
Umami , popularly referred to as savoriness, is one of the five basic tastes together with sweet, sour, bitter, and salty.-Etymology:Umami is a loanword from the Japanese meaning "pleasant savory taste". This particular writing was chosen by Professor Kikunae Ikeda from umai "delicious" and mi ...
, one of the five basic tastes of the human sense of taste
Taste
Taste is one of the traditional five senses. It refers to the ability to detect the flavor of substances such as food, certain minerals, and poisons, etc....
. Glutamic acid is often used as a food additive
Food additive
Food additives are substances added to food to preserve flavor or enhance its taste and appearance.Some additives have been used for centuries; for example, preserving food by pickling , salting, as with bacon, preserving sweets or using sulfur dioxide as in some wines...
and flavour enhancer
Flavour enhancer
Flavour enhancers are food additives commonly added to food and designed to enhance the existing flavours of products. In western cultures, the 5th taste or umami went unrecognized for a long time. It was believed that flavour enhancers did not add any new taste of their own...
in the form of its sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
salt
Salt
In chemistry, salts are ionic compounds that result from the neutralization reaction of an acid and a base. They are composed of cations and anions so that the product is electrically neutral...
monosodium glutamate
Monosodium glutamate
Monosodium glutamate, also known as sodium glutamate or MSG, is the sodium salt of glutamic acid, one of the most abundant naturally occurring non-essential amino acids....
(MSG).
Nutrient
All meats, poultry, fish, eggs, dairy products, and kombuKombu
Kombu or konbu , also called dashima or haidai , is edible kelp from the family Laminariaceae widely eaten in East Asia....
are excellent sources of glutamic acid. Some protein-rich plant foods also serve as sources. Thirty 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.
NMR Spectroscopy
In recent years, there has been much research into the use of RDCsResidual dipolar coupling
The residual dipolar coupling between two spins in a molecule occurs if the molecules in solution exhibit a partial alignment leading to an incomplete averaging of spatially anisotropic dipolar couplings....
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 GroupFufeng Group
Fufeng Group is the largest private-owned monosodium glutamate and the second largest xanthan gum producer in Mainland China. Its products include flavour enhancer, xanthan gum, fertilizer and starch sugar substitute. Its headquarter is in Shandong province. Its CEO is Mr...
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 phencyclidinePhencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
(more commonly known as PCP) antagonizes
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
glutamic acid non-competitively at the NMDA receptor. For the same reasons, sub-anaesthetic doses of ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
have strong dissociative and hallucinogenic effects. 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
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
.