α-Ketoglutaric acid (2-oxoglutaric acid) is one of two ketone derivatives of

glutaric acid Glutaric acid is the organic compound with the formula C3H6(COOH)2 . 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 ...

. The term "

ketoglutaric acid Ketoglutaric acid or oxoglutaric acid, or its conjugate base, the carboxylate ketoglutarate or oxoglutarate, may refer to the following chemical compounds: * α-Ketoglutaric acid, an intermediate in the citric acid cycle The citric acid cycle (C ...

," when not further qualified, almost always refers to the alpha variant. β-Ketoglutaric acid varies only by the position of the ketone

functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the re ...

, and is much less common. Its

carboxylate In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...

, α-ketoglutarate also called 2-oxoglutarate, is an important biological compound. It is the

keto acid In organic chemistry, keto acids or ketoacids (also called oxo acids or oxoacids) are organic compounds that contain a carboxylic acid group () and a ketone group ().Franz Dietrich Klingler, Wolfgang Ebertz "Oxocarboxylic Acids" in Ullmann's En ...

produced by

deamination Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases. In the human body, deamination takes place primarily in the liver, however it can also occur in the kidney. In situations of ...

of glutamate, and is an intermediate in the

Krebs cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...

Functions

Alanine transaminase

The enzyme

alanine transaminase Alanine transaminase (ALT) is a transaminase enzyme (). It is also called alanine aminotransferase (ALT or ALAT) and was formerly called serum glutamate-pyruvate transaminase or serum glutamic-pyruvic transaminase (SGPT) and was first characte ...

converts α-ketoglutarate and L-alanine to L-glutamate and pyruvate, respectively, as a reversible process.

Krebs cycle

α-Ketoglutarate is a key intermediate in the

, coming after

isocitrate Isocitric acid is a structural isomer of citric acid. Since citric acid and isocitric acid are structural isomers, they share similar physical and chemical properties. Due to these similar properties, it is difficult to separate the isomers. Salt ...

and before succinyl CoA.

Anaplerotic reactions Anaplerotic reactions, a term coined by Hans Kornberg and originating from the Greeἀνά 'up' anπληρόω 'to fill', are chemical reactions that form intermediates of a metabolic pathway. Examples of such are found in the citric acid cycle (TC ...

can replenish the cycle at this juncture by synthesizing α-ketoglutarate from transamination of glutamate, or through action of

glutamate dehydrogenase Glutamate dehydrogenase (GLDH, GDH) is an enzyme observed in both prokaryotes and eukaryotic mitochondria. The aforementioned reaction also yields ammonia, which in eukaryotes is canonically processed as a substrate in the urea cycle. Typical ...

on glutamate.

Formation of amino acids

Glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...

is synthesized from glutamate by

glutamine synthetase Glutamine synthetase (GS) () is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine: Glutamate + ATP + NH3 → Glutamine + ADP + phosphate Glutam ...

, which utilizes adenosine triphosphate to form glutamyl phosphate; this intermediate is attacked by ammonia as a nucleophile giving glutamine and inorganic phosphate. Proline, arginine, and lysine (in some organisms) are other amino acids synthesized as well. These three amino acids derive from glutamate with the addition of further steps or enzymes to facilitate reactions.

Nitrogen transporter

Another function is to combine with

nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...

released in cells, 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 is a chemical reaction that transfers an amino group to a ketoacid to form new amino acids. This pathway is responsible for the deamination of most amino acids. This is one of the major degradation pathways which convert essential ...

) and carried to the liver where the

urea cycle The urea cycle (also known as the ornithine cycle) is a cycle of Biochemistry, biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. 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 gamma-aminobutyric acid. It is reported that high

ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...

and/or high nitrogen levels may occur with high

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

intake, excessive aluminum exposure,

Reye's syndrome Reye syndrome is a rapidly worsening encephalopathy, brain disease. Symptoms of Reye syndrome may include vomiting, personality changes, confusion, seizures, and loss of consciousness. While hepatotoxicity, liver toxicity typically occurs in the ...

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...

, and

urea cycle disorder Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important r ...

. It plays a role in

detoxification Detoxification or detoxication (detox for short) is the physiological or medicinal removal of toxic substances from a living organism, including the human body, which is mainly carried out by the liver. Additionally, it can refer to the period of ...

of ammonia in brain.

Relationship to molecular oxygen

Acting as a co-substrate for α-ketoglutarate-dependent hydroxylase, it also plays important function in oxidation reactions involving molecular oxygen. Molecular oxygen (O₂) directly

oxidize Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

s many compounds to produce useful products in an organism, such as antibiotics, in reactions catalyzed by

oxygenase An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 (as in air) to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14. Discoverers Oxygenases were disco ...

s. In many oxygenases, α-ketoglutarate helps the reaction by being oxidized with the main substrate.

EGLN1 Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2), or prolyl hydroxylase domain-containing protein 2 (PHD2), is an enzyme encoded by the ''EGLN1'' gene. It is also known as Egl nine homolog 1. PHD2 is a α-ketoglutarate/2-oxoglutarate-depe ...

, one of the α-ketoglutarate-dependent oxygenases, is an O₂ sensor, informing the organism the oxygen level in its environment. In combination with molecular oxygen, alpha-ketoglutarate is one of the requirements for the hydroxylation of proline to hydroxyproline in the production of type 1 collagen.

Antioxidant

α-Ketoglutarate, which is released by several cell types, decreases the levels of

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3%� ...

, and the α-ketoglutarate was depleted and converted to succinate in cell culture media.

Longevity

Studies have linked α-ketoglutarate with increased lifespan in nematode worms and increased healthspan/lifespan in mice.

Immune regulation

A study showed that in glutamine deprived conditions, α-ketoglutarate promotes naïve CD4+ T cell differentiation into TH1 whilst inhibiting their differentiation into anti-inflammatory Treg cells.

Enzyme cofactor

α-Ketoglutarate has been shown to be a cofactor for demethylases that contain the Jumonji C (JmjC) domain.

Production

α-Ketoglutarate can be produced by: * Oxidative decarboxylation of

isocitrate dehydrogenase Isocitrate dehydrogenase (IDH) () and () is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a s ...

* Oxidative deamination of glutamate by

* From

galacturonic acid -Galacturonic acid is a sugar acid, an oxidized form of galactose, -galactose. It is the main component of pectin, in which it exists as the polymer polygalacturonic acid.Debra Mohnen "Pectin structure and biosynthesis" Current Opinion in Plant B ...

by the organism Agrobacterium tumefaciens Alpha-ketoglutarate can be used to produce: * Creatine-alpha ketoglutarate

Interactive pathway map

References

{{DEFAULTSORT:Ketoglutaric Acid, Alpha- Dicarboxylic acids Alpha-keto acids Citric acid cycle compounds