α-Ketoglutaric acid

α-Ketoglutaric acid (2-oxoglutaric acid) is a keto acid.

α-Ketoglutaric acid^[1]

Names
Preferred IUPAC name 2-Oxopentanedioic acid
Other names 2-Ketoglutaric acid alpha-Ketoglutaric acid 2-Oxoglutaric acid Oxoglutaric acid
Identifiers
CAS Number	328-50-7^Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:30915^Y
ChemSpider	50^Y
DrugBank	DB02926^N
ECHA InfoCard	100.005.756
IUPHAR/BPS	3636
KEGG	C00026^Y
MeSH	alpha-ketoglutaric+acid
PubChem CID	51
UNII	8ID597Z82X^Y
CompTox Dashboard (EPA)	DTXSID5033179
InChI InChI=1S/C5H6O5/c6-3(5(9)10)1-2-4(7)8/h1-2H2,(H,7,8)(H,9,10)^Y Key: KPGXRSRHYNQIFN-UHFFFAOYSA-N^Y InChI=1/C5H6O5/c6-3(5(9)10)1-2-4(7)8/h1-2H2,(H,7,8)(H,9,10) Key: KPGXRSRHYNQIFN-UHFFFAOYAN
SMILES O=C(O)C(=O)CCC(=O)O
Properties
Chemical formula	C5H6O5
Molar mass	146.098 g·mol^−1
Melting point	115 °C (239 °F; 388 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). N verify (what is ^YN ?) Infobox references

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 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.

Functions

Alanine transaminase

The enzyme alanine transaminase converts α-ketoglutarate and L-alanine to L-glutamate and pyruvate, respectively, as a reversible process.^{[citation needed]}

Krebs cycle

α-Ketoglutarate is a key intermediate in the Krebs cycle, coming after isocitrate and before succinyl CoA. Anaplerotic reactions can replenish the cycle at this juncture by synthesizing α-ketoglutarate from transamination of glutamate, or through action of glutamate dehydrogenase on glutamate.^{[citation needed]}

Formation of amino acids

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.^[2] These three amino acids derive from glutamate with the addition of further steps or enzymes to facilitate reactions.^[3]

Nitrogen transporter

Another function is to combine with nitrogen released in cells, therefore preventing nitrogen overload.^[4]

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.^[5]

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.^[6]

It is reported that high ammonia and/or high nitrogen levels may occur with high protein intake, excessive aluminium exposure, Reye's syndrome, cirrhosis, and urea cycle disorder.^[7]

It plays a role in detoxification of ammonia in brain.^[8][9][10]

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.^{[citation needed]}

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.^[11]

Supplementation

Longevity

Studies have linked α-ketoglutarate with increased lifespan in nematode worms^[12] and increased healthspan/lifespan in mice.^[13][14][15]

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.^[16]

Enzyme cofactor

α-Ketoglutarate has been shown to be a cofactor for demethylases that contain the Jumonji C (JmjC) domain.^[17][18]

Production

α-Ketoglutarate can be produced by:

• Oxidative decarboxylation of isocitrate by isocitrate dehydrogenase
• Oxidative deamination of glutamate by glutamate dehydrogenase
• From galacturonic acid by the organism Agrobacterium tumefaciens^[19]

Alpha-ketoglutarate can be used to produce:

• Creatine-alpha ketoglutarate

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|alt=TCACycle_WP78 edit]]

TCACycle_WP78 edit

1. The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".

See also

• 2OG-dependent dioxygenases

References

1. Merck Index, 13th Edition, 5320.
2. 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. PMID 10074354.
3. Schousboe, Arne; Scafidi, Susanna; Bak, Lasse K.; Waagepetersen, Helle S.; McKenna, Mary C. (2014). "Glutamate metabolism in the brain focusing on astrocytes". Advances in Neurobiology. 11: 13–30. doi:10.1007/978-3-319-08894-5_2. ISBN 978-3-319-08893-8. ISSN 2190-5215. PMC 4667713. PMID 25236722.
4. Katayama, Kazuhiro (2004-12-01). "Ammonia metabolism and hepatic encephalopathy". Hepatology Research. 30: 73–80. doi:10.1016/j.hepres.2004.08.013. ISSN 1386-6346.
5. Li, Tao; Kootstra, Anna B.; Fotheringham, Ian G. (2002-07-01). "Nonproteinogenic α-Amino Acid Preparation Using Equilibrium Shifted Transamination". Organic Process Research & Development. 6 (4): 533–538. doi:10.1021/op025518x. ISSN 1083-6160.
6. Kaneko, T.; Mizuno, N. (August 1994). "Glutamate-synthesizing enzymes in GABAergic neurons of the neocortex: a double immunofluorescence study in the rat". Neuroscience. 61 (4): 839–849. doi:10.1016/0306-4522(94)90407-3. ISSN 0306-4522. PMID 7838383.
7. "Hyperammonemia: What It Is, Causes, Symptoms & Treatment". Cleveland Clinic. Retrieved 2023-11-03.
8. . Archived from the original on 2014-05-19. Retrieved 2014-05-19.
9. 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. PMID 15921824. S2CID 916739.
10. Hares, P; James, IM; Pearson, RM (May–Jun 1978). "Effect of ornithine alpha ketoglutarate (OAKG) on the response of brain metabolism to hypoxia in the dog". Stroke: A Journal of Cerebral Circulation. 9 (3): 222–4. doi:10.1161/01.STR.9.3.222. PMID 644619.
11. 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. PMID 21281600.
12. Chin, RM; Fu, X; Pai, MY; Vergnes, L; Hwang, H; Deng, G; Diep, S; Lomenick, B; Meli, VS; Monsalve, GC; Hu, E; Whelan, SA; Wang, JX; Jung, G; Solis, GM; Fazlollahi, F; Kaweeteerawat, C; Quach, A; Nili, M; Krall, AS; Godwin, HA; Chang, HR; Faull, KF; Guo, F; Jiang, M; Trauger, SA; Saghatelian, A; Braas, D; Christofk, HR; Clarke, CF; Teitell, MA; Petrascheck, M; Reue, K; Jung, ME; Frand, AR; Huang, J (2014). "The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR". Nature. 510 (7505): 397–401. Bibcode:2014Natur.510..397C. doi:10.1038/nature13264. PMC 4263271. PMID 24828042.
13. Kaiser 1, Jocelyn (2020-09-01). "Bodybuilding supplement promotes healthy aging and extends life span, at least in mice". Science | AAAS. Retrieved 2020-09-01.{{cite web}}: CS1 maint: numeric names: authors list (link)
14. "A metabolite produced by the body increases lifespan and dramatically compresses late-life morbidity in mice". BUCK. Retrieved 2020-09-01.
15. Shahmirzadi, Azar Asadi; Edgar, Daniel; Liao, Chen-Yu (2020-09-01). "Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice". Cell Metabolism. Retrieved 2020-09-20.
16. Klysz, Dorota; Tai, Xuguang (29 September 2015). "Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation". Science Signaling. 8 (396): ra97. doi:10.1126/scisignal.aab2610. PMID 26420908.
17. Tsukada, Yu-ichi; Fang, Jia; Erdjument-Bromage, Hediye; Warren, Maria E.; Borchers, Christoph H.; Tempst, Paul; Zhang, Yi (February 2006). "Histone demethylation by a family of JmjC domain-containing proteins". Nature. 439 (7078): 811–816. doi:10.1038/nature04433. ISSN 1476-4687. PMID 16362057. S2CID 4415889.
18. Yamane, Kenichi; Toumazou, Charalambos; Tsukada, Yu-ichi; Erdjument-Bromage, Hediye; Tempst, Paul; Wong, Jiemin; Zhang, Yi (2006-05-05). "JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor". Cell. 125 (3): 483–495. doi:10.1016/j.cell.2006.03.027. ISSN 0092-8674. PMID 16603237.
19. Richard, Peter; Hilditch, Satu (2009). "d-Galacturonic acid catabolism in microorganisms and its biotechnological relevance". Applied Microbiology and Biotechnology. 82 (4): 597–604. doi:10.1007/s00253-009-1870-6. ISSN 0175-7598. PMID 19159926. S2CID 22671282.