α-Ketoglutaric acid (2-oxoglutaric acid) is a
keto acid.
Its
carboxylate, α-ketoglutarate (also called 2-oxoglutarate), is an important biological compound. It is produced by
deamination of
glutamate, and is an intermediate in the
Krebs cycle.
The enzyme
alanine transaminase (also termed alanine aminotransferase and glutamate pyruvate transaminase)
catalyzes, i.e. converts, 1) α-ketoglutarate to
L-glutamate and 2)L-alanine to
pyruvate. Both of these catalyzed reactions are fully
reversible, i.e., run in both the forward and reverse directions.[2]
Glutamine is synthesized from glutamate by
glutamine synthetase, 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.[3] These three amino acids derive from glutamate with the addition of further steps or enzymes to facilitate reactions.[4]
Nitrogen transporter
Another function is to combine with
nitrogen released in cells, therefore preventing nitrogen overload.[5]
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.[6]
Molecular oxygen (O2) directly
oxidizes many compounds to produce useful products in an organism, such as
antibiotics, in reactions catalyzed by
oxygenases. In many oxygenases, α-ketoglutarate helps the reaction by being oxidized with the main
substrate.
EGLN1, one of the α-ketoglutarate-dependent oxygenases, is an O2 sensor, informing the organism of the oxygen level in its environment.[clarification needed]
In combination with molecular oxygen, alpha-ketoglutarate is one of the requirements for the hydroxylation of proline to
hydroxyproline in the production of many
collagens.[citation needed]
Antioxidant
α-Ketoglutarate, which is released by several cell types, decreases the levels of
hydrogen peroxide, and the α-ketoglutarate was depleted and converted to
succinate in cell culture media.[12]
Supplementation
Longevity
Studies have linked α-ketoglutarate with increased lifespan in
nematode worms[13] and increased healthspan/lifespan in mice.[14][15][16]
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.[17]
Enzyme cofactor
α-Ketoglutarate has been shown to be a cofactor for
demethylases that contain the Jumonji C (JmjC) domain.[18][19]
^Ledwidge, Richard; Blanchard, John S. (1999). "The Dual Biosynthetic Capability of N-Acetylornithine Aminotransferase in Arginine and Lysine Biosynthesis†". Biochemistry. 38 (10): 3019–3024.
doi:
10.1021/bi982574a.
PMID10074354.
^Schousboe, Arne; Scafidi, Susanna; Bak, Lasse K.; Waagepetersen, Helle S.; McKenna, Mary C. (2014). "Glutamate Metabolism in the Brain Focusing on Astrocytes". Glutamate and ATP at the Interface of Metabolism and Signaling in the Brain. Advances in Neurobiology. Vol. 11. pp. 13–30.
doi:
10.1007/978-3-319-08894-5_2.
ISBN978-3-319-08893-8.
ISSN2190-5215.
PMC4667713.
PMID25236722.
^Ott, P; Clemmesen, O; Larsen, FS (Jul 2005). "Cerebral metabolic disturbances in the brain during acute liver failure: from hyperammonemia to energy failure and proteolysis". Neurochemistry International. 47 (1–2): 13–8.
doi:
10.1016/j.neuint.2005.04.002.
PMID15921824.
S2CID916739.
^Long, L; Halliwell, B (2011). "Artefacts in cell culture: α-Ketoglutarate can scavenge hydrogen peroxide generated by ascorbate and epigallocatechin gallate in cell culture media". Biochemical and Biophysical Research Communications. 406 (1): 20–24.
doi:
10.1016/j.bbrc.2011.01.091.
PMID21281600.