Ketoglutaric acid
Encyclopedia
α-Ketoglutaric acid is one of two ketone
derivatives of glutaric acid
. (The term "ketoglutaric acid," when not further qualified, almost always refers to the alpha variant. β-Ketoglutaric acid
varies only by the position of the ketone
functional group
, and is much less common.)
Its anion, α-ketoglutarate (α-KG, also called oxo-glutarate) is an important biological compound. It is the keto acid
produced by de-amination
of glutamate, and is an intermediate in the Krebs cycle.
can replenish the cycle at this juncture by synthesizing α-ketoglutarate from transamination of glutamate, or through action of glutamate dehydrogenase
on glutamate.
is synthesized from glutamate by glutamine synthase, which utilizes an ATP to form glutamyl phosphate; this intermediate is attacked by ammonia as a nucleophile giving glutamine and inorganic phosphate.
released in the cell, therefore preventing nitrogen overload.
α-Ketoglutarate is one of the most important nitrogen transporters in metabolic pathways. The amino groups of amino acids are attached to it by transamination
and carried to the liver where the urea cycle
takes place.
α-Ketoglutarate is transaminated, along with glutamine, to form the excitatory neurotransmitter
glutamate. Glutamate can then be decarboxylated
(requiring vitamin B6
) into the inhibitory neurotransmitter GABA
.
It is reported that high ammonia
and/or high nitrogen levels may occur with high protein
intake, excessive aluminum exposure, Reye's syndrome
, cirrhosis
, and urea cycle disorder
.
Molecular oxygen (O2) directly oxidizes many compounds to produce useful products in an organism, such as antibiotic
s, etc., in reactions catalyzed by oxygenase
s. In many oxygenases, α-ketoglutarate helps the reaction by being oxidized together with the main substrate
. In fact, one of the α-ketoglutarate-dependent oxygenases is an O2 sensor, informing the organism the oxygen level in its environment.
and to body builders as AKG or a-KG with the claim that it improves peak athletic performance. This claim is based on studies that show excess ammonia
in the body can combine with alpha-ketoglutarate, reducing problems associated with ammonia toxicity. However, the only studies that show alpha-ketoglutarate can reduce ammonia toxicity have been performed in hemodialysis patients.
Alpha-ketoglutarate can be used to produce:
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
derivatives of glutaric acid
Glutaric acid
Glutaric acid is the organic compound with the formula HO2C3CO2H. Although the related "linear" dicarboxylic acids adipic and succinic acids are water-soluble only to a few percent at room temperature, the water-solubility of glutaric acid is over 50%....
. (The term "ketoglutaric acid," when not further qualified, almost always refers to the alpha variant. β-Ketoglutaric acid
Acetonedicarboxylic acid
Acetonedicarboxylic acid or 3-oxoglutaric acid is a simple carboxylic acid, which may be used as a building block in organic chemistry....
varies only by the position of the ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
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...
, and is much less common.)
Its anion, α-ketoglutarate (α-KG, also called oxo-glutarate) is an important biological compound. It is the 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...
produced by de-amination
Amination
Amination is the process by which an amine group is introduced into an organic molecule. Enzymes which catalyse this reaction, are termed aminases. This can occur in a number of ways including reaction with ammonia or another amine such as an alkylation, reductive amination and the Mannich reaction...
of glutamate, and is an intermediate in the Krebs cycle.
Krebs cycle
α-Ketoglutarate is a key intermediate in the Krebs cycle, coming after isocitrate and before succinyl CoA. Anaplerotic reactionsAnaplerotic reactions
Anaplerotic reactions are those that form intermediates of a metabolic pathway. Examples of such are found in the Tricarboxylic acid Cycle...
can replenish the cycle at this juncture by synthesizing α-ketoglutarate from transamination of glutamate, or through action of 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...
on glutamate.
Formation of amino acids
GlutamineGlutamine
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...
is synthesized from glutamate by glutamine synthase, which utilizes an ATP to form glutamyl phosphate; this intermediate is attacked by ammonia as a nucleophile giving glutamine and inorganic phosphate.
Nitrogen transporter
Another function is to combine with nitrogenNitrogen
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...
released in the cell, therefore preventing nitrogen overload.
α-Ketoglutarate is one of the most important nitrogen transporters in metabolic pathways. The amino groups of amino acids are attached to it by transamination
Transamination
There are two chemical reactions known as transamination . The first is the reaction between an amino acid and an alpha-keto acid...
and carried to the liver where the urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
takes place.
α-Ketoglutarate is transaminated, along with glutamine, to form the excitatory 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...
glutamate. Glutamate can then be decarboxylated
Carboxylation
Carboxylation in chemistry is a chemical reaction in which a carboxylic acid group is introduced in a substrate. The opposite reaction is decarboxylation.-Carboxylation in organic chemistry:In organic chemistry many different protocols exist for carboxylation...
(requiring vitamin B6
Vitamin B6
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation...
) into the inhibitory neurotransmitter GABA
Gabâ
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...
.
It is reported that high ammonia
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...
and/or high nitrogen levels may occur with high protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
intake, excessive aluminum exposure, Reye's syndrome
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...
, cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, and urea cycle disorder
Urea cycle disorder
An urea cycle disorder or urea cycle defect is a genetic disorder caused by a deficiency of one of the enzymes in the urea cycle which is responsible for removing ammonia from the blood stream. The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein...
.
Relationship to molecular oxygen
Acting as a co-substrate, it also plays important function in oxidation reactions involving molecular oxygen.Molecular oxygen (O2) directly oxidizes many compounds to produce useful products in an organism, such as antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s, etc., in reactions catalyzed by oxygenase
Oxygenase
An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14....
s. In many oxygenases, α-ketoglutarate helps the reaction by being oxidized together with the main substrate
Substrate (chemistry)
In chemistry, a substrate is the chemical species being observed, which reacts with a reagent. This term is highly context-dependent. In particular, in biochemistry, an enzyme substrate is the material upon which an enzyme acts....
. In fact, one of the α-ketoglutarate-dependent oxygenases is an O2 sensor, informing the organism the oxygen level in its environment.
Dietary supplement
α-Ketoglutaric acid is sold as a dietary supplementDietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
and to body builders as AKG or a-KG with the claim that it improves peak athletic performance. This claim is based on studies that show excess ammonia
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...
in the body can combine with alpha-ketoglutarate, reducing problems associated with ammonia toxicity. However, the only studies that show alpha-ketoglutarate can reduce ammonia toxicity have been performed in hemodialysis patients.
Production
α-Ketoglutarate can be produced by:- Oxidative decarboxylationOxidative decarboxylationPyruvate decarboxylation is the far from equilibrium biochemical reaction that uses pyruvate to form acetyl-CoA, releasing NADH, a reducing equivalent, and carbon dioxide via decarboxylation...
of isocitrate by isocitrate dehydrogenaseIsocitrate dehydrogenaseIsocitrate dehydrogenase and , also known as IDH, is an enzyme that participates in the citric acid cycle. It catalyzes the third step of the cycle: the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate and CO2 while converting NAD+ to NADH...
; - Oxidative deaminationOxidative deaminationOxidative deamination is a form of deamination that generates oxoacids in the liver.The presence of nitrous acid can cause transition mutations, by converting cytosine to uracil. Primarily occurs in the liver and kidneys.-In Urea cycle:...
of glutamate by glutamate dehydrogenaseGlutamate dehydrogenaseGlutamate 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...
.
Alpha-ketoglutarate can be used to produce:
- Creatine-alpha ketoglutarateCreatine-alpha ketoglutarateCreatine-alpha-ketoglutarate is a salt formed from alpha-ketoglutaric acid and creatine. It is sold as a fitness supplement; however, its effects are experimentally unproven....