Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Α-Ketoglutaric acid: Difference between pages
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{{DISPLAYTITLE:α-Ketoglutaric acid}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|chembox}}) taken from revid [{{fullurl:Alpha-Ketoglutaric_acid|oldid=471060605}} 471060605] of page [[Alpha-Ketoglutaric_acid]] with values updated to verified values.}} |
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| verifiedrevid = |
| verifiedrevid = 477319214 |
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| Name = α-Ketoglutaric acid |
| Name = α-Ketoglutaric acid |
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| Reference = <ref>''Merck Index'', 13th Edition, '''5320'''.</ref> |
| Reference = <ref>''Merck Index'', 13th Edition, '''5320'''.</ref> |
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| ImageFile = Alpha- |
| ImageFile = Alpha-ketoglutaric acid.png |
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| ImageSize = |
| ImageSize = |
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| PIN = 2-Oxopentanedioic acid |
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| OtherNames = 2-Ketoglutaric acid<br>alpha-Ketoglutaric acid<br>2-Oxoglutaric acid<br>Oxoglutaric acid |
| OtherNames = 2-Ketoglutaric acid<br/>alpha-Ketoglutaric acid<br/>2-Oxoglutaric acid<br/>Oxoglutaric acid |
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|Section1={{Chembox Identifiers |
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| IUPHAR_ligand = 3636 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 50 |
| ChemSpiderID = 50 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
| UNII_Ref = {{fdacite|correct|FDA}} |
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| InChIKey = KPGXRSRHYNQIFN-UHFFFAOYAN |
| InChIKey = KPGXRSRHYNQIFN-UHFFFAOYAN |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = |
| ChEMBL = |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C5H6O5/c6-3(5(9)10)1-2-4(7)8/h1-2H2,(H,7,8)(H,9,10) |
| StdInChI = 1S/C5H6O5/c6-3(5(9)10)1-2-4(7)8/h1-2H2,(H,7,8)(H,9,10) |
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| CASNo_Ref = {{cascite|correct|CAS}} |
| CASNo_Ref = {{cascite|correct|CAS}} |
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| CASNo = 328-50-7 |
| CASNo = 328-50-7 |
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| PubChem = 51 |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 30915 |
| ChEBI = 30915 |
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| DrugBank_Ref = {{drugbankcite| |
| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| DrugBank = |
| DrugBank = DB02926 |
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| SMILES = O=C(O)C(=O)CCC(=O)O |
| SMILES = O=C(O)C(=O)CCC(=O)O |
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| MeSHName = alpha-ketoglutaric+acid |
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|Section2={{Chembox Properties |
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| C=5 | H=6 | O=5 |
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| Formula = C<sub>5</sub>H<sub>6</sub>O<sub>5</sub> |
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| Appearance = |
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| MolarMass = 146.11 g/mol |
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| Density = |
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| MeltingPtC = 115 |
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| MeltingPt = 113.5 |
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'''α-Ketoglutaric acid''' (also termed 2-oxoglutaric acid) is a [[dicarboxylic acid]], i.e., a short-chain fatty acid containing two [[carboxyl group]]s (carboxy groups notated as {{chem2|CO2H}}) with C, O, and H standing for [[carbon]], [[oxygen]], and [[hydrogen]], respectively (see adjacent figure). However, almost all animal tissues and [[extracellular fluids]] have a [[pH]] above 7. At these [[Base (chemistry)|basic]] pH levels α-ketoglutaric acid exists almost exclusively as its [[conjugate base]]. That is, it has two negative [[electric charge]]s due to its release of positively charged hydrogen (i.e., {{chem2|H+}}) from both of its now negatively charged carboxy groups, {{chem2|CO2-}} (see [[Conjugate (acid-base theory)|Conjugate acid-base theory]]). This double negatively charge molecule is referred to as '''α-ketoglutarate''' or 2-oxoglutarate.<ref name="pmid23378250">{{cite journal | vauthors = Chinopoulos C | title = Which way does the citric acid cycle turn during hypoxia? The critical role of α-ketoglutarate dehydrogenase complex | journal = Journal of Neuroscience Research | volume = 91 | issue = 8 | pages = 1030–43 | date = August 2013 | pmid = 23378250 | doi = 10.1002/jnr.23196 | url = }}</ref> |
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[[Acetonedicarboxylic acid|β-Ketoglutaric acid]] (also termed 3-oxoglutaric acid and acetonedicarboxlic acid) and its conjugate base, β-Ketoglutarate, differ from α-ketoglutaric acid and α-ketoglutarate by the position of their ketone, i.e., carbon–oxygen double bond (C=O). β-Ketoglutaric acid's and β-ketoglutarate's C=O is on the second carbon from a {{chem2|CO2H}} whereas α-ketoglutaric acid's and α-ketoglutarate's C=O is on a carbon adjacent to a {{chem2|CO2H}}. "Ketoglutaric acid" and "ketoglutarate", when not qualified as α or β, almost always refers respectively to α-ketoglutaric acid or α-ketoglutarate.<ref name="pmid23378250"/> β-Ketoglutarate does not have the biological actions that α-ketoglutarate has; it is even suggested to inhibit at least one action of α-ketoglutarate (see the following section titled, "β-Ketoglutaric acid and TET-2").<ref name="pmid37830116">{{cite journal | vauthors = Bhatkar D, Ananda N, Lokhande KB, Khunteta K, Jain P, Hebale A, Sarode SC, Sharma NK | title = Organic Acids Derived from Saliva-amalgamated Betel Quid Filtrate Are Predicted as a Ten-eleven Translocation-2 Inhibitor | journal = Journal of Cancer Prevention | volume = 28 | issue = 3 | pages = 115–130 | date = September 2023 | pmid = 37830116 | pmc = 10564634 | doi = 10.15430/JCP.2023.28.3.115 | url = }}</ref> β-Ketoglutaric acid is used to synthesize other compounds (see [[Acetonedicarboxylic acid#Applications|applications of β-ketoglutaric acid]]) such as [[cyclohexenone]] which is itself widely used to synthesize other compounds.<ref name="pmid25968341">{{cite journal | vauthors = Quintard A, Rodriguez J | title = Synergistic Cu-amine catalysis for the enantioselective synthesis of chiral cyclohexenones | journal = Chemical Communications | volume = 51 | issue = 46 | pages = 9523–6 | date = June 2015 | pmid = 25968341 | doi = 10.1039/c5cc02987b | url = }}</ref> |
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α-Ketoglutarate is an [[Reaction intermediate|intermediate]] in the [[citric acid cycle]]; this cycle supplies the energy used by cells.<ref name="pmid23378250"/> It is also an intermediate in or product of several other [[metabolic pathway]]s.<ref name="pmid23378250"/><ref name="pmid26759695">{{cite journal | vauthors = Wu N, Yang M, Gaur U, Xu H, Yao Y, Li D | title = Alpha-Ketoglutarate: Physiological Functions and Applications | journal = Biomolecules & Therapeutics | volume = 24 | issue = 1 | pages = 1–8 | date = January 2016 | pmid = 26759695 | pmc = 4703346 | doi = 10.4062/biomolther.2015.078 | url = }}</ref> These include its being a component of metabolic pathways that: make key [[amino acids]] and in the process regulate the cellular levels of carbon, [[nitrogen]], and [[ammonia]];<ref name="pmid26759695"/> reduce the cellular levels of potentially toxic [[reactive oxygen species]];<ref name="pmid29750149">{{cite journal | vauthors = Liu S, He L, Yao K | title = The Antioxidative Function of Alpha-Ketoglutarate and Its Applications | journal = BioMed Research International | volume = 2018 | issue = | pages = 3408467 | date = 2018 | pmid = 29750149 | pmc = 5884300 | doi = 10.1155/2018/3408467 | doi-access = free | url = }}</ref><ref name="pmid35500655">{{cite journal | vauthors = Kroupina K, Bémeur C, Rose CF | title = Amino acids, ammonia, and hepatic encephalopathy | journal = Analytical Biochemistry | volume = 649 | issue = | pages = 114696 | date = July 2022 | pmid = 35500655 | doi = 10.1016/j.ab.2022.114696 | hdl = 1866/26644 | url = | hdl-access = free }}</ref> and synthesize the [[neurotransmitter]] [[gamma-aminobutyric acid]].<ref name="pmid7838383">{{cite journal | vauthors = Kaneko T, Mizuno N | title = Glutamate-synthesizing enzymes in GABAergic neurons of the neocortex: a double immunofluorescence study in the rat | journal = Neuroscience | volume = 61 | issue = 4 | pages = 839–49 | date = August 1994 | pmid = 7838383 | doi = 10.1016/0306-4522(94)90407-3 | url = }}</ref> It also acts as a direct stimulator of, or [[Cofactor (biochemistry)|cofactor]] (i.e., required for but does not itself stimulate) for various cellular functions as defined in studies that are primarily preclinical (i.e., conducted in [[Model organism|animal models of disease]] or on animal or human tissues). These studies have provided evidence that α-ketoglutarate contributes to regulating: kidney function;<ref name="pmid23934124">{{cite journal | vauthors = Tokonami N, Morla L, Centeno G, Mordasini D, Ramakrishnan SK, Nikolaeva S, Wagner CA, Bonny O, Houillier P, Doucet A, Firsov D | title = α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism | journal = The Journal of Clinical Investigation | volume = 123 | issue = 7 | pages = 3166–71 | date = July 2013 | pmid = 23934124 | pmc = 3696567 | doi = 10.1172/JCI67562 | url = }}</ref> the benefits that resistance exercise has in reducing obesity, strengthening muscles, and preventing muscle atrophy;<ref name="pmid32104923">{{cite journal | vauthors = Yuan Y, Xu P, Jiang Q, Cai X, Wang T, Peng W, Sun J, Zhu C, Zhang C, Yue D, He Z, Yang J, Zeng Y, Du M, Zhang F, Ibrahimi L, Schaul S, Jiang Y, Wang J, Sun J, Wang Q, Liu L, Wang S, Wang L, Zhu X, Gao P, Xi Q, Yin C, Li F, Xu G, Zhang Y, Shu G | title = Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation | journal = The EMBO Journal | volume = 39 | issue = 7 | pages = e103304 | date = April 2020 | pmid = 32104923 | pmc = 7110140 | doi = 10.15252/embj.2019103304 | url = }}</ref> glucose tolerance as defined in [[glucose tolerance test]]s;<ref name="pmid35507647">{{cite journal | vauthors = Yuan Y, Zhu C, Wang Y, Sun J, Feng J, Ma Z, Li P, Peng W, Yin C, Xu G, Xu P, Jiang Y, Jiang Q, Shu G | title = α-Ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling | journal = Science Advances | volume = 8 | issue = 18 | pages = eabn2879 | date = May 2022 | pmid = 35507647 | pmc = 9067931 | doi = 10.1126/sciadv.abn2879 | bibcode = 2022SciA....8N2879Y | url = }}</ref> aging and the development of changes that are associated with aging including old age-related disorders and diseases;<ref name="pmid32877690">{{cite journal | vauthors = Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, Asadi Shahmirzadi A, Wiley CD, Gan G, Kim DE, Kasler HG, Kuehnemann C, Kaplowitz B, Bhaumik D, Riley RR, Kennedy BK, Lithgow GJ | title = Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice | journal = Cell Metabolism | volume = 32 | issue = 3 | pages = 447–456.e6 | date = September 2020 | pmid = 32877690 | pmc = 8508957 | doi = 10.1016/j.cmet.2020.08.004 | url = }}</ref> the development and/or progression of certain types of cancer and [[inflammation]]s;<ref name="pmid36050314">{{cite journal | vauthors = Manni W, Jianxin X, Weiqi H, Siyuan C, Huashan S | title = JMJD family proteins in cancer and inflammation | journal = Signal Transduction and Targeted Therapy | volume = 7 | issue = 1 | pages = 304 | date = September 2022 | pmid = 36050314 | pmc = 9434538 | doi = 10.1038/s41392-022-01145-1 | url = }}</ref> and the [[Cellular differentiation|differentiation]] of immature [[T cells]] into mature T cells.<ref name="pmid26420908">{{cite journal | vauthors = Klysz D, Tai X, Robert PA, Craveiro M, Cretenet G, Oburoglu L, Mongellaz C, Floess S, Fritz V, Matias MI, Yong C, Surh N, Marie JC, Huehn J, Zimmermann V, Kinet S, Dardalhon V, Taylor N | title = Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation | journal = Science Signaling | volume = 8 | issue = 396 | pages = ra97 | date = September 2015 | pmid = 26420908 | doi = 10.1126/scisignal.aab2610 | url = }}</ref> |
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==Functions== |
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===Metabolic interactions=== |
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====Citric acid cycle==== |
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α-Ketoglutarate is a component of the [[citric acid cycle]], a cyclical metabolic pathway located in the [[mitochondria]]. This cycle supplies the energy that cells need by sequentially [[metabolizing]] (indicated by <big>→</big>) citrate through seven intermediate metabolites and then converting the eighth intermediate metabolite, oxaloacetate, back to citrate:<ref name="pmid23378250"/> |
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:::::'''[[citrate]] <big>→</big> [[Aconitic acid|cis-aconitate]] <big>→</big> [[Isocitric acid|isocitrate]] <big>→</big> α-ketoglutarate <big>→</big> [[succinyl-CoA]] <big>→</big> [[succinate]] <big>→</big> [[Fumaric acid|fumarate]] <big>→</big> [[malate]] <big>→</big> [[oxaloacetate]] <big>→</big> [[citrate]]''' |
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In this cycle, the enzyme [[isocitrate dehydrogenase|isocitrate dehydrogenase 3]] converts isocitrate (isocitrate has 4 isomers of which only the (−)-d-threo-isomer is the naturally occurring isomer in the citric acid cycle.<ref name="pmid29568744">{{cite journal | vauthors = Kamzolova SV, Shamin RV, Stepanova NN, Morgunov GI, Lunina JN, Allayarov RK, Samoilenko VA, Morgunov IG | title = Fermentation Conditions and Media Optimization for Isocitric Acid Production from Ethanol by Yarrowia lipolytica | journal = BioMed Research International | volume = 2018 | issue = | pages = 2543210 | date = 2018 | pmid = 29568744 | pmc = 5820659 | doi = 10.1155/2018/2543210 | doi-access = free | url = }}</ref>) to α-ketoglutarate which in the next step is converted to succinyl-CoA by the [[oxoglutarate dehydrogenase complex]] of enzymes. Outside of the citric acid cycle, α-ketoglutarate is made by '''a)''' the enzymes [[isocitrate dehydrogenase]] 1 or 2 which remove a carboxy group from [[isocitrate]] by oxidative [[decarboxylation]] to form α-ketoglutarate; '''b)''' [[glutaminolysis]] in which the enzyme [[glutaminase]] removes the [[amino group]] (i.e., {{chem2|\sNH2}}) from [[glutamine]] to form glutamate which is converted to α-ketoglutarate by any one of three different enzymes, [[glutamate dehydrogenase]], [[alanine transaminase]], or [[aspartate transaminase]] (see [[Glutaminolysis|The glutaminolytic pathway]]s); and '''c)''' various [[pyridoxal phosphate]]-dependent [[transamination]] reactions mediated by, e.g., the [[alanine transaminase]] enzyme,<ref name="pmid19085960">{{cite journal | vauthors = Yang RZ, Park S, Reagan WJ, Goldstein R, Zhong S, Lawton M, Rajamohan F, Qian K, Liu L, Gong DW | title = Alanine aminotransferase isoenzymes: molecular cloning and quantitative analysis of tissue expression in rats and serum elevation in liver toxicity | journal = Hepatology | volume = 49 | issue = 2 | pages = 598–607 | date = February 2009 | pmid = 19085960 | pmc = 2917112 | doi = 10.1002/hep.22657 | url = }}</ref> in which glutamate is converted to α-Ketoglutarate by "donating" its {{chem2|\sNH2}} to other compounds (see [[transamination]]).<ref name="pmid26759695"/><ref name="pmid34952764">{{cite journal | vauthors = Gyanwali B, Lim ZX, Soh J, Lim C, Guan SP, Goh J, Maier AB, Kennedy BK | title = Alpha-Ketoglutarate dietary supplementation to improve health in humans | journal = Trends in Endocrinology and Metabolism | volume = 33 | issue = 2 | pages = 136–146 | date = February 2022 | pmid = 34952764 | doi = 10.1016/j.tem.2021.11.003 | hdl = 1871.1/4ada9cac-6437-44d5-ad2b-c0ee6431df3b | url = | hdl-access = free }}</ref> Acting in these pathways, α-ketoglutarate contributes to the production of amino acids such as [[glutamine]], [[proline]], [[arginine]], and [[lysine]] as well as the reduction of cellular carbon and nitrogen (i.e., N) levels; this prevents excessive levels of these two potentially toxic [[Chemical element|elements]] from accumulating in cells and tissues.<ref name="pmid29750149"/><ref name="pmid19085960"/><ref name="pmid34952764"/> The [[neurotoxin]], [[ammonia]] (i.e., {{Chem2|NH3}}), is also prevented form accumulating in tissues. In this metabolic pathway the {{chem2|\sNH2}} group on an amino acid is transferred to α-ketoglutarate; this forms the α-keto acid of the original amino acid and the amine-containing product of α-ketoglutarate, glutamate. The celllular glutamate passes into the circulation and is taken up by the liver where it delivers its acquired {{chem2|\sNH2}} group to the [[urea cycle]]. In effect, the latter pathway removes excess ammonia from the body in the form of urinary [[urea]].<ref name="pmid29750149"/><ref name="pmid35500655"/><ref>{{Cite journal |last=Katayama |first=Kazuhiro |date=2004-12-01 |title=Ammonia metabolism and hepatic encephalopathy |url=https://www.sciencedirect.com/science/article/pii/S138663460400227X |journal=Hepatology Research |volume=30 |pages=73–80 |doi=10.1016/j.hepres.2004.08.013 |pmid=15607143 |issn=1386-6346}}</ref> |
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====Reactive oxygen species==== |
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Many conditions can cause the excessive accumulation of [[reactive oxygen species]] such as the [[hydroxyl]] radical (i.e., <sup>•</sup>HO), [[hydrogen peroxide]] (i.e., H<sub>2</sub>O<sub>2</sub>), and [[superoxide anion]] (i.e., O<sub>2</sub><sup>−</sup>). These tissue-injuring oxygen species may lead to excessive inflammation, [[atherosclerosis]], [[cardiovascular diseases]], [[neurological disorders]], [[aging-associated diseases]], and various cancers. Antioxidant enzymes (i.e., [[superoxide dismutase]], [[catalase]], and [[glutathione peroxidase]]) and non-enzymatic antioxidant agents (e.g., [[glutathione]], vitamin C, and vitamin E) act to reduce the levels of these disease-causing agents. α-Ketoglutarate is one of the non-enzymatic antioxidant agents. It reacts with hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) to form [[succinate]], carbon dioxide (i.e., {{chem2|CO2}}), and water (i.e., ({{chem2|H2O}}) thereby reducing the levels of H<sub>2</sub>O<sub>2</sub>. The protective action of α-ketoglutarate in reducing the toxic effects of H<sub>2</sub>O<sub>2</sub> have been observed in ''[[Drosophila melanogaster]]'' (i.e., fruit flies), other animals, and humans. In addition, α-ketoglutarate increases the activity of [[superoxide dismutase]] which converts the highly toxic ({{chem|O|2|-}}) [[radical (chemistry)|radical]] to molecular [[oxygen]] (i.e., O<sub>2</sub>) and {{chem|H|2|O|2}}.<ref name="pmid29750149"/><ref name="pmid35500655"/> |
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====Formation of the neurotransmitter gamma-aminobutyric acid==== |
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A study conducted on the [[GABAergic]] [[neurons]] (i.e., nerve cells) in the [[neocortex]] of rat brains reported that the [[cytosol]]ic form of the [[aspartate transaminase]] enzyme metabolizes α-ketoglutarate to [[glutamate]] which in turn is metabolized by [[glutamic acid decarboxylase]] to the [[Neurotransmitter#Modulation|inhibitory neurotransmitter]] [[gamma-aminobutyric acid]]. These metabolic reactions occur at the ends of the inhibitory [[axons]] of the GABAergic neurons and result in the release of gamma-aminobutyric acid which then inhibits the activation of nearby neurons.<ref name="pmid7838383"/><ref name="pmid32002773">{{cite journal | vauthors = Robinson MB, Lee ML, DaSilva S | title = Glutamate Transporters and Mitochondria: Signaling, Co-compartmentalization, Functional Coupling, and Future Directions | journal = Neurochemical Research | volume = 45 | issue = 3 | pages = 526–540 | date = March 2020 | pmid = 32002773 | pmc = 7060825 | doi = 10.1007/s11064-020-02974-8 | url = }}</ref> |
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===Bioactions of α-Ketoglutarate=== |
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====OXGR1 receptor-dependent bioactions==== |
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OXGR1 (also known as GPR99) is a [[G protein-coupled receptor]], i.e., a [[Receptor (biochemistry)|receptor]] located on the [[Cell membrane|surface membrane of cells]] that binds certain [[Ligand (biochemistry)|ligands]] and is thereby stimulated to activate [[G proteins]] that elicit pre-programmed responses in their parent cells. OXRG1 was identified as a receptor for: '''a)''' α-ketoglutarate in 2004;<ref name="pmid36919698">{{cite journal | vauthors = Zeng YR, Song JB, Wang D, Huang ZX, Zhang C, Sun YP, Shu G, Xiong Y, Guan KL, Ye D, Wang P | title = The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response | journal = The Journal of Clinical Investigation | volume = 133 | issue = 6 | pages = | date = March 2023 | pmid = 36919698 | pmc = 10014103 | doi = 10.1172/JCI160463 | url = }}</ref><ref name="pmid38448252">{{cite journal | vauthors = Ye D, Wang P, Chen LL, Guan KL, Xiong Y | title = Itaconate in host inflammation and defense | journal = Trends in Endocrinology and Metabolism | volume = | issue = | pages = | date = March 2024 | pmid = 38448252 | doi = 10.1016/j.tem.2024.02.004 | url = }}</ref> '''b)''' three [[leukotrienes]] viz., [[leukotriene E4|leukotrienes E4]], [[leukotriene C4|C4]], and [[Leukotriene D4|D4]] in 2013.<ref name="pmid23504326">{{cite journal | vauthors = Kanaoka Y, Maekawa A, Austen KF | title = Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand | journal = The Journal of Biological Chemistry | volume = 288 | issue = 16 | pages = 10967–72 | date = April 2013 | pmid = 23504326 | pmc = 3630866 | doi = 10.1074/jbc.C113.453704 | doi-access = free | url = }}</ref><ref name="pmid31135881">{{cite journal | vauthors = Sasaki F, Yokomizo T | title = The leukotriene receptors as therapeutic targets of inflammatory diseases | journal = International Immunology | volume = 31 | issue = 9 | pages = 607–615 | date = August 2019 | pmid = 31135881 | doi = 10.1093/intimm/dxz044 | url = }}</ref> and '''c)''' [[itaconate]] in 2023.<ref name="pmid36919698"/><ref name="pmid38448252"/> These ligands have the following relative potencies in stimulating responses in OXGR1-bearing cells (Note that LTE4 can stimulate OXGR1 at concentrations far lower than those of the other four ligands): |
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:::LTE4 >> LTC4 = LTD4 > α-ketoglutarate = itaconate. |
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It may be difficult to determine if an OXGR1-stimulating agent elicits a functional response by activating OXGR1 as opposed to some other mechanism. To make this distinction, studies have shown that the action of an OXGR1-activating agent on cultured cells, cultured tissues, or animals does not occur or is reduced when these cells, tissues, or animals have been altered so that they do not express or express greatly reduced levels of the OXGR1 protein,<ref name="pmid36919698"/><ref name="pmid38448252"/><ref name="pmid23504326"/><ref name="pmid34179130">{{cite journal | vauthors = Guerrero A, Visniauskas B, Cárdenas P, Figueroa SM, Vivanco J, Salinas-Parra N, Araos P, Nguyen QM, Kassan M, Amador CA, Prieto MC, Gonzalez AA | title = α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions | journal = Frontiers in Cardiovascular Medicine | volume = 8 | issue = | pages = 644797 | date = 2021 | pmid = 34179130 | pmc = 8220822 | doi = 10.3389/fcvm.2021.644797 | doi-access = free | url = }}</ref> or when their actions are inhibited by an OXGR1 [[receptor antagonist]]s. OXGR1 is inhibited by [[Montelukast]], a well-known inhibitor of the [[cysteinyl leukotriene receptor 1]], i.e., the receptor for LTD4, LTC4, and LTE4. Montelukast also blocks the binding of these leukotrienes to, and thereby inhibits their activation of, OXGR1. One study presented evidence suggesting that α-ketoglutarate binds to OXGR1. It is assumed that Montelukast similarly blocks α-ketoglutarate's binding to, and thereby inhibits its activation of OXGR1.<ref name="pmid23504326"/><ref name="pmid34179130"/> |
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====Kidney functions==== |
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The [[pendrin]] protein promotes the [[electroneutral exchange]] of tissue [[chloride]] (Cl<sup>−</sup>) for urinary [[bicarbonate]] (HCO<sub>3</sub><sup>−</sup>) in the apical surfaces (i.e., surfaces facing the urine) of the kidney's renal β-intercalated cells (also termed type B intercalated cells) and non-α non-β intercalated cells (also termed non-A non-B intercalated cells) in the kidney's [[collecting duct system]] (i.e., CDS).<ref name="pmid38110744">{{cite journal | vauthors = Brazier F, Cornière N, Picard N, Chambrey R, Eladari D | title = Pendrin: linking acid base to blood pressure | journal = Pflugers Archiv | volume = 476 | issue = 4 | pages = 533–543 | date = April 2024 | pmid = 38110744 | doi = 10.1007/s00424-023-02897-7 | url = }}</ref> A study in mice found that OXGR1 colocalizes with [[pendrin]] in the [[Collecting duct system#Intercalated cells|β-intercalated cells and non-α non-β intercalated cells]] lining the [[tubules]] of their kidney's CDS. The intercalated cells in the CDS tubules isolated from mice used pendrin in cooperation with the [[electroneutral sodium bicarbonate exchanger 1]] protein to mediate the Cl<sup>−</sup> for HCO<sub>3</sub><sup>−</sup> exchange. α-Ketoglutarate stimulated the rate of this exchange in CDS tubules isolated from control mice (i.e., mice that had the ''Oxgr1'' gene and protein) but not in CDS tubules isolated from ''Oxgr1'' [[gene knockout]] mice (i.e., mice that lacked the ''Oxgr1'' gene and protein). This study also showed that the α-ketoglutarate in the blood of mice filtered through their kidney's [[glomeruli]] into the [[proximal tubules]] and [[loops of Henle]] where it was reabsorbed. Mice drinking water with a [[Basic (chemistry)|basic]] [[pH]] (i.e., >7) due to the addition of [[sodium bicarbonate]] and mice lacking the ''Oxgr1'' gene and protein who drink water without sodium bicarbonate had urines that were more basic (i.e., pH about 7.8) and contained higher levels of urinary α-ketoglutarate than control mice drinking water without this additive. Furthermore, ''Oxgr1'' gene knockout mice drinking sodium bicarbonate-rich water developed [[metabolic alkalosis]] (body tissue pH levels higher than normal) that was associated with blood bicarbonate levels significantly higher and blood chloride levels significantly lower than those in control mice drinking the sodium bicarbonate-rich water.<ref name="pmid23934124"/> Several other studies confirmed these findings and reported that cells in the proximal tubules of mice synthesize α-ketoglutarate and either broke it down thereby reducing its urine levels or secreted it into the tubules' lumens thereby increasing its urine levels.<ref name="pmid28771454">{{cite journal | vauthors = Grimm PR, Welling PA | title = α-Ketoglutarate drives electroneutral NaCl reabsorption in intercalated cells by activating a G-protein coupled receptor, Oxgr1 | journal = Current Opinion in Nephrology and Hypertension | volume = 26 | issue = 5 | pages = 426–433 | date = September 2017 | pmid = 28771454 | doi = 10.1097/MNH.0000000000000353 | url = }}</ref> Another study showed that '''a)''' ''[[In silico]]'' [[computer simulation]]s strongly suggested that α-ketoglutarate bound to mouse OXGPR1; '''b)''' suspensions of canal duct cells isolated from the collecting ducts, loops of Henle, [[Vasa recta (kidney)|vasa recta]], and [[interstitium]] of mouse kidneys raised their cytosolic ionic calcium, i.e., Ca<sup>2+</sup> levels in response to α-ketoglutarate but this response (which is an indicator of cell activation) was blocked by pretreating the cells with Montelukast; and '''c)''' compared to mice not treated with [[streptozotocin]], streptozotocin-induced diabetic mice (an [[animal disease model]] of [[diabetes]]) urinated only a small amount of the ionic sodium ({{chem2|Na+}}) that they drank or received by intravenous injections; Montelukast reversed this defect in the streptozotocin-pretreated mice.<ref name="pmid34179130"/> These results indicate that in mice: '''a)''' α-ketoglutarate stimulates kidney OXGR1 to activate pendrin-mediated reabsorption of sodium and chloride by type B and non-A–non-B intercalated cells; '''b)''' high [[alkaline]] (i.e., sodium bicarbonate) intake produces significant increases in urine pH and α-ketoglutarate levels and impairs secretion of bicarbonate into the CDS tubules' lumens; '''c)''' the [[Acid–base homeostasis|acid–base balance]] (i.e., levels of acids relative to their bases) in the face of high alkali intake depends on the activation of OXGR1 by α-ketoglutarate;<ref name="pmid23934124"/><ref name="pmid28771454"/> '''d)''' alkaline loading directly or indirectly stimulates α-ketoglutarate secretion into the kidney's proximal tubules where further down these tubules it activates OXGR1 and thereby the absorption and secretion of various agents that contribute to restoring a physiologically normal acid-base balance;<ref name="pmid28771454"/> and '''e)''' α-ketoglutarate stimulates OXGR1-bearing CDS cells to raise their levels of cytosolic Ca<sup>2+</sup>) and in diabetic mice (and presumably other conditions involving high levels of blood and/or urine glucose) to increase these cells uptake of {{chem2|Na+}}.<ref name="pmid23934124"/><ref name="pmid34179130"/><ref name="pmid38110744"/><ref name="pmid28771454"/> |
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====Resistance exercise, obesity, and muscle atrophy==== |
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Resistance exercise is exercising a muscle or muscle group against external resistance (see [[strength training]]). Studies have found that: '''a)''' mice feeding on a high fat or normal diet and given the resistance exercise of repeatedly climbing up a 1 [[meter]] ladder for 40 minutes had higher levels of α-ketoglutarate in their blood and 7 different muscles than non-exercising mice feeding respectively on the high fat or normal diet; '''b)''' mice conducting ladder climbing for several weeks and eating a high fat diet developed lower fat tissue masses and higher lean tissue masses than non-exercising mice on this diet; '''c)''' mice not in exercise training fed α-ketoglutarate likewise developed lower fat tissue and higher lean tissue masses than α-ketoglutarate-unfed, non-exercising mice; '''d)''' OXGR1 was strongly expressed in the mouse [[Renal medulla|adrenal gland inner medullas]] and either resistance training or oral α-ketoglutarate increased this tissue's levels of the [[mRNA]] that is responsible for the synthesis of OXGR1; '''e)''' α-ketoglutarate stimulated [[chromaffin cells]] isolated from mouse adrenal glands to release [[epinephrine]] but reduction of these cells' OXGR1 levels by [[small interfering RNA]] reduced this response; '''f)''' α-ketoglutarate increased the blood serum levels of epinephrine in mice expressing OXGR1 but not in ''Oxgr1'' gene knockout mice (i.e., mice lacking the ''OXGR1'' gene and protein); '''g)''' mice on the high fat diet challenged with α-ketoglutarate increased their blood serum levels of epinephrine and developed lower fat tissue masses and higher lean tissue masses but neither ''OXGR1'' gene knockout mice nor mice that had only their adrenal glands' ''OXGR1'' gene knocked out showed these responses; and '''h)''' ''OXGR1'' gene knockout mice fed the high fat diet developed muscle protein degradation, muscle [[atrophy]] (i.e., wasting), and falls in body weight whereas control mice did not show these fat diet-induced changes. These findings indicate that in mice resistance exercise increases muscle production as well as serum levels of α-ketoglutarate which in turn suppresses diet-induced obesity (i.e., low body fat and high lean body masses) at least in part by stimulating the OXGR1 on adrenal gland chromaffin cells to release epinephrine.<ref name="pmid32104923"/><ref name="pmid35507647"/><ref name="pmid28939592">{{cite journal | vauthors = Cai X, Yuan Y, Liao Z, Xing K, Zhu C, Xu Y, Yu L, Wang L, Wang S, Zhu X, Gao P, Zhang Y, Jiang Q, Xu P, Shu G | title = α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway | journal = FASEB Journal | volume = 32 | issue = 1 | pages = 488–499 | date = January 2018 | pmid = 28939592 | pmc = 6266637 | doi = 10.1096/fj.201700670R | doi-access = free | url = }}</ref> Another study reported that middle‐aged, i.e., 10‐month‐old, mice had lower serum levels of α-ketoglutarate than 2‐month‐old mice. Middle aged mice fed a high fat diet gained body weight and fat mass in the lower parts of their bodies and had impaired glucose tolerance as defined in glucose tolerance tests. Adding α-ketoglutarate to the drinking water of these mice inhibited the development of these changes. These results suggest that drinking the α-ketoglutarate-rich water replenished the otherwise diminished supplies of α-ketoglutarate in middle aged mice; the replenished supply of α-ketoglutarate thereby became available to suppress obesity and improve glucose tolerance.<ref name="pmid31691468">{{cite journal | vauthors = Tian Q, Zhao J, Yang Q, Wang B, Deavila JM, Zhu MJ, Du M | title = Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice | journal = Aging Cell | volume = 19 | issue = 1 | pages = e13059 | date = January 2020 | pmid = 31691468 | pmc = 6974731 | doi = 10.1111/acel.13059 | url = }}</ref> Finally, a study in rats feed a low fat or high fat diet for 27 weeks and drinking α-ketoglutarate-rich water for the last 12 weeks of this 27 week period decreased their fat issue masses and increased their whole-body insulin sensitivity as defined in glucose tolerance tests. Rats fed either of these diets but not given α-ketoglutarate-rich water did not show these changes. This study indicates that α-ketoglutarate regulates body fat mass and insulin sensitivity in rats as well as mice.<ref name="pmid31357871">{{cite journal | vauthors = Tekwe CD, Yao K, Lei J, Li X, Gupta A, Luan Y, Meininger CJ, Bazer FW, Wu G | title = Oral administration of α-ketoglutarate enhances nitric oxide synthesis by endothelial cells and whole-body insulin sensitivity in diet-induced obese rats | journal = Experimental Biology and Medicine | volume = 244 | issue = 13 | pages = 1081–1088 | date = October 2019 | pmid = 31357871 | pmc = 6775570 | doi = 10.1177/1535370219865229 | url = }}</ref> |
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===OXGR1 receptor-independent bioactions=== |
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The following actions of α-ketoglutarate have not been evaluated for their dependency on activating OXGR1 and are here assumed to be OXGR1-independent. Futures studies are needed to determine if OXGR1 contributes in whole or part to these actions of α-ketoglutarate. |
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====Aging and diseases associated with aging==== |
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α-Ketoglutarate has been reported to increase the [[maximum life span|life span]] and/or delay the development of old age-related diseases in a [[species]] of [[roundworm]]s and in mice. It nearly doubled the life span and delayed age-related deteriorations (e.g., decline in rapid, coordinated body movements) of ''[[Caenorhabditis elegans]]'' roundworms when added to their [[cell cultures]].<ref name="pmid26759695"/><ref name="pmid24828042">{{cite journal | vauthors = 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 | title = The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR | journal = Nature | volume = 510 | issue = 7505 | pages = 397–401 | date = June 2014 | pmid = 24828042 | pmc = 4263271 | doi = 10.1038/nature13264 | url = }}</ref> Similarly, mice fed a diet high in calcium-bound α-ketoglutarate had a longer life span and shorter length of time in which they suffered old age-related morbidities (e.g., increased frailty, hair loss, and changes in body weight). Cell cultures of [[splenocyte]]s (i.e., primarily [[T cells]]) from the α-ketoglutarate-fed mice produced higher levels of the anti-inflammatory [[cytokine]], [[interleukin-10]], than splenocytes from mice not fed α-ketoglutarate.<ref name="pmid32877690"/><ref name="pmid34952764"/> (Chronic low-grade inflammation which might be inhibited by interleukin-10, is associated with the development of old age-related disorders and diseases.<ref name="pmid36637079">{{cite journal | vauthors = Islam MT, Tuday E, Allen S, Kim J, Trott DW, Holland WL, Donato AJ, Lesniewski LA | title = Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age | journal = Aging Cell | volume = 22 | issue = 2 | pages = e13767 | date = February 2023 | pmid = 36637079 | pmc = 9924942 | doi = 10.1111/acel.13767 | url = }}</ref>) |
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A small and very preliminary study suggested that α-ketoglutarate may also promote longevity in humans. Fourteen females (age 64.09, range 43.49 to 72.46 years) and 28 males (age 62.78, range 41.31 to 79.57 years) volunteered to take Rejuvant® for an average period of 7 months. The Rejuvant® commercial preparations they used contained 1,000 mg of calcium α-ketoglutarate monohydrate plus either 900 mg of [[retinyl palmitate]] (a form of [[vitamin A]] containing 190 mg of calcium) for males (i.e., Rejuvant® for males) or 25 mg of [[vitamin D]] containing 190 mg of calcium for females (i.e., Rejuvant® for females).<ref name="pmid34847066">{{cite journal | vauthors = Demidenko O, Barardo D, Budovskii V, Finnemore R, Palmer FR, Kennedy BK, Budovskaya YV | title = Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test | journal = Aging | volume = 13 | issue = 22 | pages = 24485–24499 | date = November 2021 | pmid = 34847066 | pmc = 8660611 | doi = 10.18632/aging.203736 | url = }}</ref> As individuals age, their [[DNA]] develops additions of a [[methyl group]] (-{{chem2|CH3}}) to a [[cystine]] adjacent to a [[guanine]] (termed a [[CpG site#CgP island|CpG island]]) in an increasing number of CpG islands close to certain genes. These [[methylation]]s often suppress the [[Gene expression|expression]] of the genes to which they are close. Assays (termed [[epigenetic clock]] tests) that determine the presence of methylations of cystines in CpG islands for key genes have been used to define an individual's biological age.<ref name="pmid35968782">{{cite journal | vauthors = Soto-Palma C, Niedernhofer LJ, Faulk CD, Dong X | title = Epigenetics, DNA damage, and aging | journal = The Journal of Clinical Investigation | volume = 132 | issue = 16 | pages = | date = August 2022 | pmid = 35968782 | pmc = 9374376 | doi = 10.1172/JCI158446 | url = }}</ref><ref name="pmid36304336">{{cite journal | vauthors = Chen L, Ganz PA, Sehl ME | title = DNA Methylation, Aging, and Cancer Risk: A Mini-Review | journal = Frontiers in Bioinformatics | volume = 2 | issue = | pages = 847629 | date = 2022 | pmid = 36304336 | pmc = 9580889 | doi = 10.3389/fbinf.2022.847629 | doi-access = free | url = }}</ref><ref name="pmid37657418">{{cite journal | vauthors = Moqri M, Herzog C, Poganik JR, Justice J, Belsky DW, Higgins-Chen A, Moskalev A, Fuellen G, Cohen AA, Bautmans I, Widschwendter M, Ding J, Fleming A, Mannick J, Han JJ, Zhavoronkov A, Barzilai N, Kaeberlein M, Cummings S, Kennedy BK, Ferrucci L, Horvath S, Verdin E, Maier AB, Snyder MP, Sebastiano V, Gladyshev VN | title = Biomarkers of aging for the identification and evaluation of longevity interventions | journal = Cell | volume = 186 | issue = 18 | pages = 3758–3775 | date = August 2023 | pmid = 37657418 | pmc = 11088934 | doi = 10.1016/j.cell.2023.08.003 | url = }}</ref> The Rejuvant® study reported that the median and range of the biological age of females before treatment was 62.15 (range, 46.4 to 73) years and fell to 55.55 (range 33.4 to 63.7) years after an average of 7 months treatment. These values for men were 61.85 (range 41.9 to 79.7) years before and 53.3 (33 to 74.9) years after treatment.<ref name="pmid34952764"/><ref name="pmid34847066"/> Overall, the combined group of males and females showed an average fall in biological age of 8 years compared to before treatment. The ''p''-value for this difference was extraordinarily significant, i.e., 6.538x10-12, in showing that that this treatment decreased the participants' biological ages. However, the study did not: '''a)''' include a [[Placebo-controlled study|control group]] (i.e., concurrent study of individuals taking a [[placebo]] instead of Rejuvant®); '''b)''' determine if the retinyl palmitate, vitamin A, and/or calcium given with α-ketoglutarate contributed to the changes in biological ages; and '''c)''' disclose which genes were tracked for the methylation of their CpG island. The study recommended that studies need to include control groups taking a placebo or the appropriate dosages of retinyl palmitate, vitamin A, and calcium. Also, TruMe Labs, who were the maker and marketer of the biological age assay used in this study, sponsored part of the study and contributed three of its employees as authors to the study.<ref name="pmid34847066"/> |
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====Fe2+/α-ketoglutarate-dependent dioxygenase enzymes and TET enzymes==== |
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α-Ketoglutarate is a cofactor that is needed for certain enzymes in the [[Demethylase#histone-lysine demethylase|histone-lysine demethylase]] [[protein superfamily]] to become activated. This superfamily consists of two groups, the FAD-dependent amine oxidases which do not require α-ketoglutarate for activation and the Fe2+/α-ketoglutarate-dependent dioxygenases (Fe2+ is the [[ferrous]] form of iron, i.e., Fe<sup>2+</sup>). The latter group of more than 30 enzymes is classified into 7 subfamilies termed histone lysine demethylases, i.e., HDM2 to HDM7, with each subfamily having multiple members. These HDMs are characterized by containing a Jumonji C (JmjC) [[protein domain]]. They function as [[dioxygenase]]s or [[hydroxylase]]s to remove [[methyl]] groups from the [[lysine]] residues on the [[histone]]s enveloping DNA and thereby alter the expression of diverse genes.<ref name="pmid26816087">{{cite journal | vauthors = Park SY, Park JW, Chun YS | title = Jumonji histone demethylases as emerging therapeutic targets | journal = Pharmacological Research | volume = 105 | issue = | pages = 146–51 | date = March 2016 | pmid = 26816087 | doi = 10.1016/j.phrs.2016.01.026 | url = }}</ref><ref name="pmid34944554">{{cite journal | vauthors = Staehle HF, Pahl HL, Jutzi JS | title = The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies | journal = Biomolecules | volume = 11 | issue = 12 | date = December 2021 | page = 1911 | pmid = 34944554 | pmc = 8699298 | doi = 10.3390/biom11121911 | doi-access = free | url = }}</ref> These altered gene expressions lead to a wide range of changes in the functions of various cell types and thereby caused the development and/or progression of various cancers, pathological inflammations, and other disorders (see [[Alpha-ketoglutarate-dependent hydroxylases#Biological function|α-Ketoglutarate-dependent demethylase biological functions]]).<ref name="pmid36050314"/><ref name="pmid37694689">{{cite journal | vauthors = Maity J, Majumder S, Pal R, Saha B, Mukhopadhyay PK | title = Ascorbic acid modulates immune responses through Jumonji-C domain containing histone demethylases and Ten eleven translocation methylcytosine dioxygenase | journal = BioEssays | volume = 45 | issue = 11 | pages = e2300035 | date = November 2023 | pmid = 37694689 | doi = 10.1002/bies.202300035 | url = }}</ref> The [[TET enzymes]] (i.e., ten-eleven translocation (TET) methylcytosine dioxygenase family of enzymes) consists of three members, TET-1, TET-2, and TET-3. Like the Fe2+/α-ketoglutarate-dependent dioxygenases, all three TET enzymes require Fe<sup>2+</sup> and α-ketoglutarate as cofactors to become activated. Unlike the dioxygenases, however, they remove methyl groups from the 5-methylcytosines of [[DNA]] sites that regulate the expression of nearby genes. These demethylations have a variety of effects including, similar to the Fe2+/α-ketoglutarate-dependent dioxygenases, alteration of the development and/or progression of various cancers, immune responses, and other disorders (see [[TET enzymes#TET functions|functions of TET enzymes]]).<ref name="pmid35705880">{{cite journal | vauthors = Joshi K, Liu S, Breslin SJ, Zhang J | title = Mechanisms that regulate the activities of TET proteins | journal = Cellular and Molecular Life Sciences | volume = 79 | issue = 7 | pages = 363 | date = June 2022 | pmid = 35705880 | pmc = 9756640 | doi = 10.1007/s00018-022-04396-x | url = }}</ref><ref name="pmid38360546">{{cite journal | vauthors = López-Moyado IF, Ko M, Hogan PG, Rao A | title = TET Enzymes in the Immune System: From DNA Demethylation to Immunotherapy, Inflammation, and Cancer | journal = Annual Review of Immunology | volume = 42| issue = | pages = | date = February 2024 | pmid = 38360546 | doi = 10.1146/annurev-immunol-080223-044610 | url = }}</ref> |
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=====β-Ketoglutaric acid and TET-2===== |
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A recent study found that β-ketoglutaric acid was detected in the saliva of individuals chewing [[betel quid chewing|betel quid]], a complex mixture derived from [[betel nut]]s mixed with various other materials. Chronic chewing betel quid is associated with the development of certain cancers, particularly those in the [[oral cavity]]. The study showed that β-ketoglutaric acid bound to the cancer-promoting protein [[TET-2]] thereby inhibiting α-ketoglutarate's binding to this protein. Since α-ketoglutarate's binding of TET-2 is thought to be required for it to activate TET-2, the study suggested that β-ketoglutaric acid may not fulfill the requirements for TET-2 to be activatable and therefore may prove able to block α-ketoglutarate's cancer-promoting as well as inflammation-promoting and other actions that involve its activation of TET-2.<ref name="pmid37830116"/> |
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====Immune regulation==== |
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Under glutamine-deprived conditions, α-ketoglutarate promotes [[naïve T cell|naïve]] CD4+ T cells differentiation into inflammation-promoting T<sub>h</sub>1 cells while inhibiting their differentiation into inflammation-inhibiting [[Treg cell]]s thereby promoting certain inflammation responses.<ref name="pmid26420908"/> |
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== Interactive pathway map == |
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{{TCACycle_WP78|highlight=Alpha-Ketoglutaric_acid}} |
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==See also== |
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* [[2-oxoglutarate (2OG)-dependent dioxygenases|2OG-dependent dioxygenases]] |
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==References== |
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{{Reflist}} |
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{{Citric acid cycle}} |
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{{Amino acid metabolism intermediates}} |
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{{DEFAULTSORT:Ketoglutaric Acid, Alpha-}} |
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[[Category:Dicarboxylic acids]] |
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[[Category:Alpha-keto acids]] |
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[[Category:Citric acid cycle compounds]] |