ケトグルタル酸、ケトグルタール酸

関: ketoglutaric acid

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/30 21:16:50」(JST)

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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 deamination of glutamate, and is an intermediate in the Krebs cycle.

Functions

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.

Formation of amino acids

Glutamine is synthesized from glutamate by glutamine synthetase, 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 nitrogen 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.

It plays a role in detoxification of ammonia in brain.^[2]^[3]^[4]

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 antibiotics, etc., in reactions catalyzed by oxygenases. 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.

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 known to be released by several cell types, decreased the levels of hydrogen peroxide, and the α-ketoglutarate was depleted and converted to succinate in cell culture media.^[5]

Longevity

A study released on May 14, 2014 links α-ketoglutarate with significantly increased lifespan in nematode worms. ^[6]

Immune Regulation

A recent study has shown that α-ketoglutarate promotes TH1 differentiation and depletion of Glutamine (by depleting its metabolite α-ketoglutarate favors Treg differentiation. It might play a role in skewing the balance in favor of Tregs in the setting of amino acid deprivation that can be seen in the tumor microenvironment.^[7]

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.^[8]

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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|{{{bSize}}}px|alt=TCA Cycle edit]]

File:TCACycle WP78.png

TCA Cycle edit

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

References

^ Merck Index, 13th Edition, 5320.
^ Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel?
^ 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.
^ 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." (PDF). Stroke; a journal of cerebral circulation 9 (3): 222–4. doi:10.1161/01.STR.9.3.222. PMID 644619.
^ 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.
^ "The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR". Nature 510: 397–401. 2014. doi:10.1038/nature13264. PMC 4263271. PMID 24828042.
^ Klysz, Dorota; Tai, Xuguang (29 Sep 2015). "Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation". Science Signaling (American Association for the Advancement of Science) 8 (396): ra97. doi:10.1126/scisignal.aab2610. Retrieved 14 October 2015.
^ 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.

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 重症患者における栄養補給：経腸栄養 nutrition support in critically ill patients enteral nutrition
2. Chapter 3C：近位尿細管における分泌経路 chapter 3c secretory pathways in proximal tubule
3. Chapter 11A：腎臓での水排泄 chapter 11a renal hydrogen excretion
4. Chapter 3B：近位尿細管におけるナトリウム輸送能の優越性 chapter 3b primacy of sodium transport in proximal function
5. ウェルニッケ脳症 wernickes encephalopathy

English Journal

Discovery of α-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1.

Kim HJ1, Fei X2, Cho SC3, Choi BY3, Ahn HC1, Lee K1, Seo SY2, Keum YS4.
Bioorganic & medicinal chemistry letters.Bioorg Med Chem Lett.2015 Dec 1;25(23):5625-31. doi: 10.1016/j.bmcl.2015.10.034. Epub 2015 Oct 23.
Somatic heterozygous mutations of isocitrate dehydrogenase-1 (IDH1) are abundantly found in several types of cancer and strongly implicate altered metabolism in carcinogenesis. In the present study, we have identified α-mangostin as a novel selective inhibitor of mutant IDH1 (IDH1-R132H). We have o
PMID 26508549

Dysfunctional TCA-Cycle Metabolism in Glutamate Dehydrogenase Deficient Astrocytes.

Nissen JD1, Pajęcka K1, Stridh MH1, Skytt DM1, Waagepetersen HS1.
Glia.Glia.2015 Dec;63(12):2313-26. doi: 10.1002/glia.22895. Epub 2015 Jul 29.
Astrocytes take up glutamate in the synaptic area subsequent to glutamatergic transmission by the aid of high affinity glutamate transporters. Glutamate is converted to glutamine or metabolized to support intermediary metabolism and energy production. Glutamate dehydrogenase (GDH) and aspartate amin
PMID 26221781

Non-homologous functions of the AlkB homologs.

Ougland R1, Rognes T2, Klungland A3, Larsen E4.
Journal of molecular cell biology.J Mol Cell Biol.2015 Dec;7(6):494-504. doi: 10.1093/jmcb/mjv029. Epub 2015 May 23.
The DNA repair enzyme AlkB was identified in E. coli more than three decades ago. Since then, nine mammalian homologs, all members of the superfamily of alpha-ketoglutarate and Fe(II)-dependent dioxygenases, have been identified (designated ALKBH1-8 and FTO). While E. coli AlkB serves as a DNA repai
PMID 26003568

Japanese Journal

アミノ酸水酸化触媒としてのα-ケトグルタル酸依存性ジオキシゲナーゼ

日比慎,小川順
バイオサイエンスとインダストリー = Bioscience & industry 69(5), 384-386, 2011-09-01
NAID 10029466411

アミノ酸水酸化触媒としてのα-ケトグルタル酸依存性ジオキシゲナーゼ

日比慎,小川順
バイオサイエンスとインダストリー 69(5), 384-386, 2011
NAID 40018979457

Related Pictures

★リンクテーブル★

リンク元	「ケトグルタル酸」「ケトグルタール酸」「ketoglutaric acid」
拡張検索	「ketoglutarate dehydrogenase complex」「alpha-ketoglutarate dehydrogenase」「alpha-ketoglutarate」「α-ketoglutarate」

「ケトグルタル酸」

α-Ketoglutaric acid^[1]
Names
	IUPAC name 2-Oxopentanedioic acid
	Other names 2-Ketoglutaric acid; alpha-Ketoglutaric acid; 2-Oxoglutaric acid; Oxoglutaric acid
Identifiers
CAS Number	328-50-7
ChEBI	CHEBI:30915
ChEMBL	ChEMBL1686
ChemSpider	50
DrugBank	DB02926
IUPHAR/BPS	3636
Jmol interactive 3D	Image
KEGG	C00026
MeSH	alpha-ketoglutaric+acid
PubChem	51
UNII	8ID597Z82X
	InChI InChI=1S/C5H6O5/c6-3(5(9)10)1-2-4(7)8/h1-2H2,(H,7,8)(H,9,10) Key: KPGXRSRHYNQIFN-UHFFFAOYSA-N ; 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	146.11 g/mol
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).
	verify (what is ?)
	Infobox references

　　[★]

英: ketoglutaric acid、ketoglutarate
関: オキソグルタル酸、ケトグルタール酸

「ケトグルタール酸」

　　[★]

英: ketoglutaric acid、ketoglutarate
関: ケトグルタル酸、オキソグルタル酸

「ketoglutaric acid」

　　[★]

ケトグルタル酸、ケトグルタール酸

関: ketoglutarate、oxoglutarate

「ketoglutarate dehydrogenase complex」

　　[★]

ケトグルタル酸脱水素酵素複合体、ケトグルタル酸デヒドロゲナーゼ複合体

関: alpha-ketoglutarate dehydrogenase

「alpha-ketoglutarate dehydrogenase」

　　[★]

αケトグルタル酸脱水素酵素、αケトグルタル酸デヒドロゲナーゼ

関: ketoglutarate dehydrogenase complex

「alpha-ketoglutarate」

　　[★]

αケトグルタル酸

関: alpha-ketoglutaric acid

alpha-ketoglutaric acid

「α-ketoglutarate」

　　[★] α-ケトグルタル酸

同: 771

[WikiPathways-9] The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".

[1] Merck Index, 13th Edition, 5320.

[2] Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel?

[3] 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.

[4] 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." (PDF). Stroke; a journal of cerebral circulation 9 (3): 222–4. doi:10.1161/01.STR.9.3.222. PMID 644619.

[5] 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.

[doi:10.1038.2Fnature13264-6] "The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR". Nature 510: 397–401. 2014. doi:10.1038/nature13264. PMC 4263271. PMID 24828042.

[DOI:10.1126.2Fscisignal.aab2610-7] Klysz, Dorota; Tai, Xuguang (29 Sep 2015). "Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation". Science Signaling (American Association for the Advancement of Science) 8 (396): ra97. doi:10.1126/scisignal.aab2610. Retrieved 14 October 2015.

[RichardHilditch2009-8] 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.

v t e Citric acid cycle metabolic pathway
			Oxaloacetate			Malate			Fumarate			Succinate			Succinyl-CoA


Acetyl-CoA				NADH + H⁺	NAD⁺			H₂O		FADH₂	FAD		CoA + ATP(GTP)	P_i + ADP(GDP)
	+	H₂O														NADH + H⁺ + CO₂
		CoA														NAD⁺
					H₂O		H₂O			NAD(P)⁺	NAD(P)H + H⁺			CO₂


			Citrate			cis-Aconitate			Isocitrate			Oxalosuccinate			α-Ketoglutarate

匿名

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案内

案内

ketoglutarate