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| Names | |
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| Preferred IUPAC name
2-Oxopentanedioic acid | |
| Other names
2-Ketoglutaric acid
alpha-Ketoglutaric acid 2-Oxoglutaric acid Oxoglutaric acid | |
| Identifiers | |
3D model (JSmol)
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| ChEBI | |
| ChemSpider | |
| DrugBank | |
| KEGG | |
| MeSH | alpha-ketoglutaric+acid |
PubChem CID
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| UNII | |
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| Properties | |
| 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).
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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 groups (carboxy group notated as 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 basic pH levels α-ketoglutaric acid exists almost exclusively as its conjugate base. That is, it exists as a double negatively electric charged molecule due to its release of positively charged hydogen (i.e., H+) from both of its two now negatively charged carboxy groups, CO−2 (see Conjugate acid-base theory). This doubly negatively charge molecule is referred to as α-ketoglutarte or 2-oxoglutarate. α-Ketoglutarate and is an intermediate in the citric acid cycle;[2] outside of this cycle it is also made by other metabolic pathways.[2][3] β-ketoglutaric acid (also termed β-ketoglutaric acid or acetonedicarboxlic acid). β-Ketoglutaric acid/acetonedicarboxlic acid differs from α-Ketoglutaric acid by the position of its ketone, i.e., carbon–oxygen double bond (C=O), which is on the second carbon from a carboxy group. α-Ketoglutaric acid's ketone group is on the carbon adjacent to a carboxy group. "ketoglutaric acid", when not qualified as α or β, almost always refers to the α variant, i.e., the anionic form of glutaric acid|.[2] β-ketoglutaric acid (also termed β-ketoglutaric acid or acetonedicarboxlic acid) differs from α-Ketoglutaric acid by the position of its ketone, i.e., carbon–oxygen double bond (C=O), which is on the second carbon from a carboxy group. α-Ketoglutaric acid's ketone group is on the carbon adjacent to a carboxy group. ketoglutaric acid, when not qualified as α or β, almost always refers to the α variant.
Functions edit
Metabolic interactions edit
Citric acid cycle edit
α-Ketoglutarate is a component of the citric acid cycle, a cyclical metabolic pathway located in the mitochondria. This cycle supplies energy from nutrients by sequentially metabolizing (indicated by →) citrate through seven intermediate metabolites and then converting the seventh intermediate metabolite, oxaloacetate, back to citate:[2]
- citrate → cis-aconitate → isocitrate → α-ketoglutarate → succinyl-CoA → succinate → fumarate → malate → oxaloacetate → citrate
In this cycle, the enzyme isocitrate dehydrogenase 3 converts isocitrate (i.e., the (−)-d-threo-isomer of isocitrate) 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 by removal of a carboxy group by oxidative decarboxylation from isocitrate; b) the enzyme glutamate dehydrogenase's removal of the amino group, i.e., −NH2, from glutamate; and c) various pyridoxal phosphate-dependent transamination reactions mediated by, e.g., the alanine transaminase enzyme,[4], in which glutamate "donates" its amino group to other substances (see transamination).[3][5] Acting in these pathwasys, α-ketoglutarate functions to promote the formation of amino acids, such as glutamine, proline, arginine, and lysine. This in turn contributes to the regulation of cellular carbon and nitrogen usage and thereby prevents excessive levels of these two elements from accumulating in tissues.[4][5][6] For example, the amino groups of amino acids are transferred to α-ketoglutarate which is then carried to the liver where its amino groups are added to the urea cycle and removed as urea from the body.[7]
Reactive oxygen species edit
Many conditions can cause the excessive acumulation of reactive oxygen species such as the hydroxyl radical (i.e., •HO), hydrogen peroxide (i.e., H2O2), and superoxide anion (i.e., O2−). These tissue-injuring reactive 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 nonenzymatic antioxidant agents (e.g., glutathione, vitamin C, and vitamin E) act to remove the levels of these disease-causing agents. α-Ketoglutarate is one of these nonenzymatic antioxidant agents. It reacts with hydrogen peroxide to form succinate, carbon dioxide (i.e., CO2), and water (i.e., (H2O) thereby reducing the levels of H2O2. The protective action of α-ketoglutarate in reducing the toxic effects of H2O2 have been observed in Drosophila melanogaster, other animals, and humans. Furthermore, AKG increases the activity of superoxide dismutase (which convers the higly toxic superoxide anion (O−
2) anion radical to molecular oxygen (i.e.,, O2) and H
2O
2. It also lowers the levels of the toxic agent ammonia (i.e., NH3) by being metabolized to glutamate and then to glutamine in the following steps by the successive actions of two enzymes, glutamate dehydrogenase followed by glutamine synthetase:[6]
Formation of the neurotransmitter gamma-aminobutyric acid edit
A study conducted on the GABAergic neurons in the neocortex of rat brains suggested that the cytosolic form of the aspartate transaminase enzyme metabolizes α-ketoglutarate to glutamate which in turn is metabolized by glutamic acid decarboxylase to the inhibitory neurotransmiter gamma-aminobutyric acid. These metabolic reactions ocrur at the ends of the inhibitory axons and result in the releaase of gamma-aminobutyric acid and thereby inhibition of nearby neurons.[8]
Bioactions of α-Ketoglutarate edit
OXGR1 receptor receptor]] edit
OXGR1 (also known as GPR99) is a G protein-coupled receptor, i.e., a receptor located on the surface membrane of cells that binds certain agents and is thereby acivated certain G proteins and thereby ellicits pre-programmed responses in its parent cells. OXRG1 was identified as a receptor for: a) α-ketoglutarate in 2004;[9][10] b) three leukotrienes viz., leukotrienes E4, C4, and D4 in 2013.[11][12] and c) itaconate in 2023.[9][10] These ligands have the following relative potencies in stimulating responses in OXGR1-bearing cells:
- LTE4 >> LTC4 = LTD4 > α-ketoglutarate = itaconate.
Note that LTE4 is able to stimulate OXGR1 at concentrations that are far lower than those of α-ketoglutarate. Consequently, it may be difficult to determine if it or to lesser extents LTC4, LTD4, or itaconate are responsible for any particular OXGR1-dependent response.[9][10][11][13] OXGR1 is inhibited by montelukast, a well-known inhibitor of cysteinyl leukotriene receptor 1 (CysLTR1), i.e., the receptor for LTD4, LTC4, and LTE4. Montelukast blocks the bining of these leukotrienes to, and thereby inhibits thier activation of OXGR1. It is assumed that this drug similary blocks α-ketoglutaratethe's bining and activation of OXGR1.[11][13]
Kidney functions edit
A study in mice found that OXGR1 colocalizes with pendrin in the β-intercalated cells and non-α non-β intercalated cells lining the tubules of their kidneys' collecting duct system (i.e., CDS). The intercalated cells in the CDS tubules isolated from mice used pendrin in cooperation with the electroneutral sodium bicarbonate exchanger 1 protein, to transport bicarbonate, i.e., HCO−
3, into the CDS tubules' lumens (i.e., inside space of a tubule) in exchange for absorbing chloride (i.e., (Cl−) from these lumens. α-Ketoglutarate stimulatd the rate of this exchange in CDS's isolated from control mice (i.e., mice that had the Oxgr1 gene) but not in CDS's from Oxgr1 gene knockout mice (i.e., mice lacking the Oxgr1 gene). The 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 may be reabsorbed. Mice drinking water with a basic pH (i.e., >7) due to the addition of sodium bicarbonate had urines that were more basic (i.e., pH about 7.8) and had higher levels of urinary α-ketoglutarate than control mice drinking water with no additive. Oxgr1 gene knockout mice drinking water without sodium bicarbonate likewise had urines that were basic and had high α-ketoglutarate levels. Oxgr1 gene knockout mice drinking sodium bicarbonate-rich water developed metabolic alkalosis that was assoicated with blood bicarbinate levels significantly higher and blood chloride levels significantly lower than those in control mice drinking sodium bicarbinate-rich water.[14] Several other studies have confirmed these findings and reported that cells in the proximal tubules of mice synthesize α-ketoglutartate and either break it down thereby reducing its urine levels or secrete it into the tubules' lumens therby increasing its urine levels. Dietary alkaline loading is associated with increases in the secretion of α-ketoglutartate into proximal tubules.[15] Finally, a more recent study showed that a) In silico computer studies strongly suggested that α-ketoglutartate bound to mouse OXGPR1; b) suspensions of canal duct cells isolated from the collecting ducts, loops of Henle, [vasa recta, and interstitium of mouse kidneys raised their cytosolic ionic calcium (i.e., (Ca2+) levels in response to α-ketoglutarate (0.1 micromole/liter) but this responses was blocked by pretreating the cells with montelucast; 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 (Na+) that they drank or recieved by intravenous injections but momtelucast reversed this defect in the streptocotocin-pre treated mice.[13] These results indicate that in mice: a) α-ketoglutarate stimulates kidney OXGR1 to activate pendrin-mediated reabsorption of sodium and cloride by type B and non-A–non-B intercalated cells; b) high alkaline (i.e., sodium bicarbinate) intake produces significant increases in urine pH and α-Ketoglutarate levels and impaired secrteion of bicarbonate into the CDS lumens; c) the acid-base equilibrium (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; d) the actions of α-ketoglutarate in the kidney involve pendrin.[14][15] e) alkaline loading directly or indiredtly stimulates α-ketoglutartate secretion into the kidney's proximal tubules where further down these tubules it activates OXGR1 and thereby the absorption and secretion of various agents and contributing to acid-base equilibrium;[15] and f) α-ketoglutartate stimulates OXGR1-bearing CDS cells to raise their cytosolic Ca2+) levels and in diabetic mice (and presumably other conditions involving high levels of glucose in the blood and urine) apparently increases their uptake of Na+.[13]
Kidney stones and nephrocalcinosis edit
Majmunda et al. identified 6 indiviuals from different families that had a history of forming calcium-containing kidney stones ((also termed nephrolithiasis) and/or nephrocalcinosis (i.e., the deposition of calcium-containing material throughout the kidney). Each of these individuals had deleterious dominant variants in their OXGR1 gene. These variant OXGR1 genes appeared to be totally inactive genes. Thus, inactivation of the OXGR1 gene is a candidate for causing human calcium-containing nephrolithiasis and nephrocalcinosis.[16]
Aging and diseases associated with aging edit
α-Ketoglutarate increased the life span and/or delayed the development of diseases acquired in old age. It nearly doubled the life span and delayed age-related deterioratoins (e.g., decline in rapid coordinated body movements) of Caenorhabditis elegans roundworms when added to their cell cultures.[3][17] Similarly, mice fed a diet high in calciium-bound α-ketoglutarate had a longr life span and shorter lenths of time in which they suffered old age-related morbidities such as increases frailty, hair loss, changes in body weight. Cell cultures of splenocytes (i.e., primarily T cells) from α-ketoglutarate-fed mice produced higher levels of the anti-inflammatory cytokine, interleukin-10 than splenocytes from mice not fed α-ketoglutarate.[5][18] And, a small and very preliminary study suggestsed that α-ketoglutarate may 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) volinteered to take Rejuvant® for an average period of 7 months. Rejuvant® commercial preparations contain 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 used 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).[19] As individuals age, their DNA shows additions of a methyl group (-CH3) to a cystine adjacent to a guanine (termed a CpG island) in an increasing number of CpG islands that are close to certain genes. These methylations often suppresses the expression of the genes to which they are close. Assays (termed epigenetic clock tests) on the presence of methylations of cystines in CpG islands for key genes have been used to define an individual's biological age.[20][21] The study reported that the median and range of the biological age of females before treament was 62.15, 46.4 to 73 years and fell to 55.55, 33.4 to 63.7 years after an avererage of 7 months treatmene. These values for men were 61.85, 41.9 to 79.7 years before and 53.3, 33 to 74.9 years after treatment.[5][19] Overall, the combined group of males and females showed an average fall in biological age of 8 years (p-value=6.538x10-12) after compared to before treatment. However, the study did not include a control group (i.e., concurrant study of individuals taking a placebo instead of Rejuvant®) and lacked studies to determine if the retinyl palmitate, vitamin A, and/or calcium given with α-ketoglutarate contributed to the changes in biological ages. The study did recommend that these studies need to be done in future studies.[19] Also, TruMe Labs was the maker and marketer of the assay used in this study, sponsored part of this study, and contributed three of its employees as authors of the study.[19]
Fe2+/α-ketoglutarate-dependent dioxygenase enzymes and TET enzymes edit
α-Ketoglutarate is a cofactor needed to activate (i.e., required for but does not activate) certain enzymes in the histone-lysine demethylase superfamily. This superfamiimly consists of two groups, the flavin adenine dinucleotide (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., Fe2+). 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 memebers. These HDMs are chacterized by having a Jumonji C (JmjC) protein domain. They function as dioxygenases or hydroxylases to remove methyl groups from the lysine residues on the histones enveloping DNA and thereby alter the expression of diverse genes.[22][23] These altered gene expressions lead to a wide range changes in cell functions including the development and/or progression of various cancers and inflammatory responses (see α-Ketoglutarate-dependent demethylase biological functions).[24][25] The TET enzymes (i.e., ten-eleven translocation (TET) methylcytosine dioxygenase family of enzymes) consists of three members, TET1, TET2, and TET3. Like the Fe2+/α-ketoglutarate-dependent dioxygenases, all three TET enzymes require Fe2+ and α-ketoglutarate as cofactors to become activacted. Unlike the deoxygenases, however, they remove methyl groups from the 5-methylcytosines of DNA sites that regulate the expression of nearby genes. These demethylations have a varity of effects including, similar to the Fe2+/α-ketoglutarate-dependent dioxygenases, alteration of the development and/or progression of various cancerss and immune responses (see functions of TET enzymes).[26][27]
Resistance exercise, obesity, and muscle atrophy edit
Resistance exercise is exercising a muscle or muscle group against external resistance (see strength training). Studies have found that: a) mice fed a normal or high fat diet given the resistence exercise of repeatedly climbing up a 1 meter ladder for 40 minutes had significantly higher levels of α-ketoglutarate in their blood serum and 7 different muscles than unxercised mice on the same diet; b) mice conducting ladder climbing for several weeks and eating a high fat diet developed lower fat tissue masses and higher lean tisse masses than non-exercising mice on this diet; c) mice not in exercise training fed α-ketoglutarate also developed lower fat tissue and higher lean tissue masses than α-ketoglutarate-unfed, non-exercisng mice; d) OXGR1 was strongly expressed in the adrenal gland's inner medulla of mice and resistance training or oral α-ketoglutara increased the expresson of the mRNA for OXGR1 in this tissue; 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 OXGR1 protein); g) mice on the high fat diet challanged with α-ketoglutarate increased their blood serum levels of epinephrine and develooped lower fat tissue masses and higher lean tisse masses but neither OXGR1 gene knockout mice nor mice that had only their adrenal glands' OXGR1 gene knocked out showed these responses to this diet; and h) unlike control mice, OXGR1 gene knockout mice fed the high fat diet developed muscle protein degradation, muscle atrophy (i.e., wasting) and falls in body weight. These findings indicate that in mice: resistance exercise increases mouse muscle production and serum levels of α-ketoglutarate which in turn suppresses diet-induced obesity (i.e., low body fat and high lean body masses) by stimulating the OXGR1 on adrenal gland chromaffin cells to release epinepherine; [28][29] Other studies have reported that middle‐aged, i.e., 10‐month‐old, mice had lower serum levels of α-ketoglutarate than young. i.e., 2‐month‐old, mice. Middle aged mice fed a high fat diet gained lower body weight and fat mass and had impaired glucose tolerance as defined in glucose tolerance test. The addition of α-ketoglutarate to the drinking water of this mice inhibited the development of these changes. Studies suggested that the effect of adding α-ketoglutarate to the drinking to replenshed the supply of of α-ketoglutarate which in turn acted as a cofactor for permitting the activation of one or more TET enzymes (see previous section).[30]
Immune regulation edit
Under glutamine-deprived conditions, α-ketoglutarate promotes naïve CD4+ T cells differentiation into inflammation-promoting Th1 cells while inhibiting their differentiation into inflammation-inhibiting Treg cells thereby promoting certain inflammation responses.[31]
Interactive pathway map edit
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ^ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".
See also edit
References edit
- ^ Merck Index, 13th Edition, 5320.
- ^ a b c d Chinopoulos C (August 2013). "Which way does the citric acid cycle turn during hypoxia? The critical role of α-ketoglutarate dehydrogenase complex". Journal of Neuroscience Research. 91 (8): 1030–43. doi:10.1002/jnr.23196. PMID 23378250.
- ^ a b c Wu N, Yang M, Gaur U, Xu H, Yao Y, Li D (January 2016). "Alpha-Ketoglutarate: Physiological Functions and Applications". Biomolecules & Therapeutics. 24 (1): 1–8. doi:10.4062/biomolther.2015.078. PMC 4703346. PMID 26759695.
- ^ a b Yang RZ, Park S, Reagan WJ, Goldstein R, Zhong S, Lawton M, Rajamohan F, Qian K, Liu L, Gong DW (February 2009). "Alanine aminotransferase isoenzymes: molecular cloning and quantitative analysis of tissue expression in rats and serum elevation in liver toxicity". Hepatology (Baltimore, Md.). 49 (2): 598–607. doi:10.1002/hep.22657. PMC 2917112. PMID 19085960.
- ^ a b c d Gyanwali B, Lim ZX, Soh J, Lim C, Guan SP, Goh J, Maier AB, Kennedy BK (February 2022). "Alpha-Ketoglutarate dietary supplementation to improve health in humans". Trends in Endocrinology and Metabolism: TEM. 33 (2): 136–146. doi:10.1016/j.tem.2021.11.003. PMID 34952764.
- ^ a b Liu S, He L, Yao K (2018). "The Antioxidative Function of Alpha-Ketoglutarate and Its Applications". BioMed Research International. 2018: 3408467. doi:10.1155/2018/3408467. PMC 5884300. PMID 29750149.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ 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. PMID 15607143.
- ^ 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. S2CID 19178915.
- ^ a b c Zeng YR, Song JB, Wang D, Huang ZX, Zhang C, Sun YP, Shu G, Xiong Y, Guan KL, Ye D, Wang P (March 2023). "The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response". The Journal of Clinical Investigation. 133 (6). doi:10.1172/JCI160463. PMC 10014103. PMID 36919698.
- ^ a b c Ye D, Wang P, Chen LL, Guan KL, Xiong Y (March 2024). "Itaconate in host inflammation and defense". Trends in Endocrinology and Metabolism: TEM. doi:10.1016/j.tem.2024.02.004. PMID 38448252. Cite error: The named reference "pmid38448252" was defined multiple times with different content (see the help page).
- ^ a b c Kanaoka Y, Maekawa A, Austen KF (April 2013). "Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand". The Journal of Biological Chemistry. 288 (16): 10967–72. doi:10.1074/jbc.C113.453704. PMC 3630866. PMID 23504326.
- ^ Sasaki F, Yokomizo T (August 2019). "The leukotriene receptors as therapeutic targets of inflammatory diseases". International Immunology. 31 (9): 607–615. doi:10.1093/intimm/dxz044. PMID 31135881.
- ^ a b c d 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 (2021). "α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions". Frontiers in Cardiovascular Medicine. 8: 644797. doi:10.3389/fcvm.2021.644797. PMC 8220822. PMID 34179130.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b Tokonami N, Morla L, Centeno G, Mordasini D, Ramakrishnan SK, Nikolaeva S, Wagner CA, Bonny O, Houillier P, Doucet A, Firsov D (July 2013). "α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism". The Journal of Clinical Investigation. 123 (7): 3166–71. doi:10.1172/JCI67562. PMC 3696567. PMID 23934124.
- ^ a b c Grimm PR, Welling PA (September 2017). "α-Ketoglutarate drives electroneutral NaCl reabsorption in intercalated cells by activating a G-protein coupled receptor, Oxgr1". Current Opinion in Nephrology and Hypertension. 26 (5): 426–433. doi:10.1097/MNH.0000000000000353. PMID 28771454.
- ^ Majmundar AJ, Widmeier E, Heneghan JF, Daga A, Wu CW, Buerger F, Hugo H, Ullah I, Amar A, Ottlewski I, Braun DA, Jobst-Schwan T, Lawson JA, Zahoor MY, Rodig NM, Tasic V, Nelson CP, Khaliq S, Schönauer R, Halbritter J, Sayer JA, Fathy HM, Baum MA, Shril S, Mane S, Alper SL, Hildebrandt F (March 2023). "OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis". Genetics in Medicine : Official Journal of the American College of Medical Genetics. 25 (3): 100351. doi:10.1016/j.gim.2022.11.019. PMC 9992313. PMID 36571463.
- ^ 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 (June 2014). "The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR". Nature. 510 (7505): 397–401. doi:10.1038/nature13264. PMC 4263271. PMID 24828042.
- ^ 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 (September 2020). "Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice". Cell Metabolism. 32 (3): 447–456.e6. doi:10.1016/j.cmet.2020.08.004. PMC 8508957. PMID 32877690.
- ^ a b c d Demidenko O, Barardo D, Budovskii V, Finnemore R, Palmer FR, Kennedy BK, Budovskaya YV (November 2021). "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". Aging. 13 (22): 24485–24499. doi:10.18632/aging.203736. PMC 8660611. PMID 34847066.
- ^ Soto-Palma C, Niedernhofer LJ, Faulk CD, Dong X (August 2022). "Epigenetics, DNA damage, and aging". The Journal of Clinical Investigation. 132 (16). doi:10.1172/JCI158446. PMC 9374376. PMID 35968782.
- ^ Chen L, Ganz PA, Sehl ME (2022). "DNA Methylation, Aging, and Cancer Risk: A Mini-Review". Frontiers in Bioinformatics. 2: 847629. doi:10.3389/fbinf.2022.847629. PMC 9580889. PMID 36304336.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Park SY, Park JW, Chun YS (March 2016). "Jumonji histone demethylases as emerging therapeutic targets". Pharmacological Research. 105: 146–51. doi:10.1016/j.phrs.2016.01.026. PMID 26816087.
- ^ Staehle HF, Pahl HL, Jutzi JS (December 2021). "The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies". Biomolecules. 11 (12). doi:10.3390/biom11121911. PMC 8699298. PMID 34944554.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Manni W, Jianxin X, Weiqi H, Siyuan C, Huashan S (September 2022). "JMJD family proteins in cancer and inflammation". Signal Transduction and Targeted Therapy. 7 (1): 304. doi:10.1038/s41392-022-01145-1. PMC 9434538. PMID 36050314.
- ^ Maity J, Majumder S, Pal R, Saha B, Mukhopadhyay PK (November 2023). "Ascorbic acid modulates immune responses through Jumonji-C domain containing histone demethylases and Ten eleven translocation (TET) methylcytosine dioxygenase". BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology. 45 (11): e2300035. doi:10.1002/bies.202300035. PMID 37694689.
- ^ Joshi K, Liu S, Breslin SJ, Zhang J (June 2022). "Mechanisms that regulate the activities of TET proteins". Cellular and Molecular Life Sciences : CMLS. 79 (7): 363. doi:10.1007/s00018-022-04396-x. PMC 9756640. PMID 35705880.
- ^ López-Moyado IF, Ko M, Hogan PG, Rao A (February 2024). "TET Enzymes in the Immune System: From DNA Demethylation to Immunotherapy, Inflammation, and Cancer". Annual Review of Immunology. doi:10.1146/annurev-immunol-080223-044610. PMID 38360546.
- ^ 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 (January 2018). "α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway". FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 32 (1): 488–499. doi:10.1096/fj.201700670R. PMC 6266637. PMID 28939592.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ 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 (April 2020). "Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation". The EMBO Journal. 39 (7): e103304. doi:10.15252/embj.2019103304. PMC 7110140. PMID 32104923.
- ^ Tian Q, Zhao J, Yang Q, Wang B, Deavila JM, Zhu MJ, Du M (January 2020). "Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice". Aging Cell. 19 (1): e13059. doi:10.1111/acel.13059. PMC 6974731. PMID 31691468.
- ^ 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.
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