2-Hydroxyglutarate in Cancer Cells

. 2020 Nov 01 ; 33 (13) : 903-926. [epub] 20200122

Jazyk angličtina Země Spojené státy americké Médium print-electronic

Typ dokumentu časopisecké články, práce podpořená grantem, přehledy

Perzistentní odkaz   https://www.medvik.cz/link/pmid31847543

Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1)R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2)R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to "intermediate" 0.01-0.1 mM 2HG levels, for example, in breast carcinoma compared with 10-8M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics.

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Achouri Y, Noël G, Vertommen D, Rider MH, Veiga-Da-Cunha M, and Van Schaftingen E. Identification of a dehydrogenase acting on D-2-hydroxyglutarate. Biochem J 381: 35–42, 2004 PubMed PMC

Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O'Donnell P, Grigoriadis A, Diss T, Eskandarpour M, Presneau N, Hogendoorn PC, Futreal A, Tirabosco R, and Flanagan AM. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224: 334–343, 2011 PubMed

Amaya ML and Pollyea DA. Targeting the IDH2 pathway in acute myeloid leukemia. Clin Cancer Res 24: 4931–4936, 2018 PubMed

An Z, Tiwari V, Baxter J, Levy M, Hatanpaa KJ, Pan E, Maher EA, Patel TR, Mickey BE, and Choi C. 3D high-resolution imaging of 2-hydroxyglutarate in glioma patients using DRAG-EPSI at 3T in vivo. Magn Reson Med 81: 795–802, 2019 PubMed PMC

Ansó E, Weinberg SE, Diebold LP, Thompson BJ, Malinge S, Schumacker PT, Liu X, Zhang Y, Shao Z, Steadman M, Marsh KM, Xu J, Crispino JD, and Chandel NS. The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nat Cell Biol 19: 614–625, 2017 PubMed PMC

Bailey PSJ and Nathan JA. Metabolic regulation of hypoxia-inducible transcription factors: the role of small molecule metabolites and iron. MDPI Biomed 6: 60, 2018 PubMed PMC

Ballester LY, Lu G, Zorofchian S, Vantaku V, Putluri V, Yan Y, Arevalo O, Zhu P, Riascos RF, Sreekumar A, Esquenazi Y, Putluri N, and Zhu JJ. Analysis of cerebrospinal fluid metabolites in patients with primary or metastatic central nervous system tumors. Acta Neuropathol Commun 6: 85, 2018 PubMed PMC

Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, and von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116: 597–602, 2008 PubMed

Berrington A, Voets NL, Larkin SJ, de Pennington N, Mccullagh J, Stacey R, Schofield CJ, Jezzard P, Clare S, Cadoux-Hudson T, Plaha P, Ansorge O, and Emir UE. A comparison of 2-hydroxyglutarate detection at 3 and 7 T with long-TE semi-LASER. NMR Biomed 31: 3886, 2018 PubMed

Bleeker FE, Atai NA, Lamba S, Jonker A, Rijkeboer D, Bosch KS, Tigchelaar W, Troost D, Vandertop WP, Bardelli A, and Van Noorden CJ. The prognostic IDH1(R132) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol 119: 487–494, 2010 PubMed PMC

Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, Frattini M, Molinari F, Knowles M, Cerrato A, Rodolfo M, Scarpa A, Felicioni L, Buttitta F, Malatesta S, Marchetti A, and Bardelli A. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 30: 7–11, 2009 PubMed

Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS, Schenkein DP, Hezel AF, Ancukiewicz M, Liebman HM, Kwak EL, Clark JW, Ryan DP, Deshpande V, Dias-Santagata D, Ellisen LW, Zhu AX, and Iafrate AJ. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 17: 72–79, 2012 PubMed PMC

Bottcher M, Renner K, Berger R, Mentz K, Thomas S, Cardenas-Conejo ZE, Dettmer K, Oefner PJ, Mackensen A, Kreutz M, and Mougiakakos D. D-2-hydroxyglutarate interferes with HIF-1alpha stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization. Oncoimmunology 7: e1445454, 2018 PubMed PMC

Brand MD. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic Biol Med 100: 14–31, 2016 PubMed

Brooks E, Wu X, Hanel A, Nguyen S, Wang J, Zhang JH, Harrison A, and Zhang W. Identification and characterization of small-molecule inhibitors of the R132H/R132H mutant isocitrate dehydrogenase 1 homodimer and R132H/wild-type heterodimer. J Biomol Screen 19: 1193–1200, 2014 PubMed

Brunner AM, Neuberg DS, Wander SA, Sadrzadeh H, Ballen KK, Amrein PC, Attar E, Hobbs GS, Chen YB, Perry A, Connolly C, Joseph C, Burke M, Ramos A, Galinsky I, Yen K, Yang H, Straley K, Agresta S, Adamia S, Borger DR, Iafrate A, Graubert TA, Stone RM, and Fathi AT. Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia. Cancer 125: 541–549, 2019 PubMed

Budczies J, Brockmöller SF, Müller BM, Barupal DK, Richter-Ehrenstein C, Kleine-Tebbe A, Griffin JL, Orešič M, Dietel M, Denkert C, and Fiehn O. Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism. J Proteomics 94: 279–288, 2013 PubMed

Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, Alansary D, Sonner JK, Green E, Deumelandt K, Kilian M, Neftel C, Uhlig S, Kessler T, von Landenberg A, Berghoff AS, Marsh K, Steadman M, Zhu D, Nicolay B, Wiestler B, Breckwoldt MO, Al-Ali R, Karcher-Bausch S, Bozza M, Oezen I, Kramer M, Meyer J, Habel A, Eisel J, Poschet G, Weller M, Preusser M, Nadji-Ohl M, Thon N, Burger MC, Harter PN, Ratliff M, Harbottle R, Benner A, Schrimpf D, Okun J, Herold-Mende C, Turcan S, Kaulfuss S, Hess-Stumpp H, Bieback K, Cahill DP, Plate KH, Hänggi D, Dorsch M, Suvà ML, Niemeyer BA, von Deimling A, Wick W, and Platten M. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med 24: 1192–1203, 2018 PubMed

Burr SP, Costa ASH, Grice GL, Timms RT, Lobb IT, Freisinger P, Dodd RB, Dougan G, Lehner PJ, Frezza C, and Nathan JA. Mitochondrial protein lipoylation and the 2-oxoglutarate dehydrogenase complex controls hif1a stability in aerobic conditions. Cell Metab 24: 740–752, 2016 PubMed PMC

Cairns RA and Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov 3: 730–741, 2013 PubMed

Carbonneau M, M Gagné L, Lalonde ME, Germain MA, Motorina A, Guiot MC, Secco B, Vincent EE, Tumber A, Hulea L, Bergeman J, Oppermann U, Jones RG, Laplante M, Topisirovic I, Petrecca K, Huot MÉ, and Mallette FA. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway. Nat Commun 7: 12700, 2016 PubMed PMC

Ceccarelli C, Grodsky NB, Ariyaratne N, Colman RF, and Bahnson BJ. Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism. J Biol Chem 277: 43454–43462, 2002 PubMed

Chakraborty AA, Laukka T, Myllykoski M, Ringel AE, Booker MA, Tolstorukov MY, Meng YJ, Meier SR, Jennings RB, Creech AL, Herbert ZT, McBrayer SK, Olenchock BA, Jaffe JD, Haigis MC, Beroukhim R, Signoretti S, Koivunen P, and Kaelin WG Jr. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363: 1217–1222, 2019 PubMed PMC

Chalmers RA, Lawson AM, Watts RW, Tavill AS, Kamerling JP, Hey E, and Ogilvie D. D-2-Hydroxyglutaric aciduria: case report and biochemical studies. J Inherit Metab Dis 3: 11–15, 1980 PubMed

Chen F, Bian K, Tang Q, Fedeles BI, Singh V, Humulock ZT, Essigmann JM, and Li D. Oncometabolites d- and l-2-hydroxyglutarate inhibit the AlkB family DNA repair enzymes under physiological conditions. Chem Res Toxicol 30: 1102–1110, 2017 PubMed PMC

Chen JY, Lai YS, Tsai HJ, Kuo CC, Yen BL, Yeh SP, Sun HS, and Hung WC. The oncometabolite R-2-hydroxyglutarate activates NFkappaB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells. Sci Rep 6: 32428, 2016 PubMed PMC

Chen D, Yu J, and Zhang L. Necroptosis: an alternative cell dech program defending against cancer. Biochim Biophys Acta 1865, : 228–236, 2016 PubMed PMC

Chiang S, Weigelt B, Wen HC, Pareja F, Raghavendra A, Martelotto LG, Burke KA, Basili T, Li A, Geyer FC, Piscuoglio S, Ng CK, Jungbluth AA, Balss J, Pusch S, Baker GM, Cole KS, von Deimling A, Batten JM, Marotti JD, Soh HC, McCalip BL, Serrano J, Lim RS, Siziopikou KP, Lu S, Liu X, Hammour T, Brogi E, Snuderl M, Iafrate AJ, Reis-Filho JS, and Schnitt SJ. IDH2 mutations define a unique subtype of breast cancer with altered nuclear polarity. Cancer Res 76: 7118–7129, 2016 PubMed PMC

Chisolm AD and Weinmann AS. Connections between metabolism and epigenetics in programming cellular differentiation. Annu Rev Immunol 36: 221–246, 2018 PubMed

Choi C, Ganji SK, DeBerardinis RJ, Hatanpaa KJ, Rakheja D, Kovacs Z, Yang XL, Mashimo T, Raisanen JM, Marin-Valencia I, Pascual JM, Madden CJ, Mickey BE, Malloy CR, Bachoo RM, and Maher EA. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18: 624–629, 2012 PubMed PMC

Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, Leung IK, Li XS, Woon EC, Yang M, McDonough MA, King ON, Clifton IJ, Klose RJ, Claridge TD, Ratcliffe PJ, Schofield CJ, and Kawamura A. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep 12, 463–469, 2011 PubMed PMC

Clerkin JS, Naughton R, Quiney C, and Cotter TG. Mechanisms of ROS modulated cell survival during carcinogenesis. Cancer Lett 266: 30–36, 2008 PubMed

Colvin H, Nishida N, Konno M, Haraguchi N, Takahashi H, Nishimura J, Hata T, Kawamoto K, Asai A, Tsunekuni K, Koseki J, Mizushima T, Satoh T, Doki Y, Mori M, and Ishii H. Oncometabolite D-2-hydroxyglurate directly induces epithelial-mesenchymal transition and is associated with distant metastasis in colorectal cancer. Sci Rep 6: 36289, 2016 PubMed PMC

Dando I, Pozza ED, Ambrosini G, Torrens-Mas M, Butera G, Mullappilly N, Pacchiana R, Palmieri M, and Donadelli M. Oncometabolites in cancer aggressiveness and tumour repopulation. Biol Rev Camb Philos Soc 94: 1530–1546, 2019 PubMed

Dang L and Su SM. Mutation and (R)-2-hydroxyglutarate: from basic discovery to therapeutics development. Annu Rev Biochem 86: 305–331, 2017 PubMed

Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, and Su SM. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462: 739–744, 2009 PubMed PMC

DeBerardinis RJ and Chandel NS. Fundamentals of cancer metabolism. Sci Adv 2: e1600200, 2016 PubMed PMC

Deng G, Shen J, Yin M, McManus J, Mathieu M, Gee P, He T, Shi C, Bedel O, McLean LR, Le-Strat F, Zhang Y, Marquette JP, Gao Q, Zhang B, Rak A, Hoffmann D, Rooney E, Vassort A, Englaro W, Li Y, Patel V, Adrian F, Gross S, Wiederschain D, Cheng H, and Licht S. Selective inhibition of mutant isocitrate dehydrogenase 1 (IDH1) via disruption of a metal binding network by an allosteric small molecule. J Biol Chem 290: 762–774, 2015 PubMed PMC

Dikalova AE, Itani HA, Nazarewicz RR, McMaster WG, Flynn CR, Uzhachenko R, Fessel JP, Gamboa JL, Harrison DG, and Dikalov SI. Sirt3 impairment and SOD2 hyperacetylation in vascular oxidative stress and hypertension. Circ Res 121: 564–574, 2017 PubMed PMC

DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, and Kantarjian HM. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 378: 2386–2398, 2018 PubMed

Dodo M, Kitamura H, Shima H, Saigusa D, Wati SM, Ota N, Katsuoka F, Chiba H, Okae H, Arima T, Igarashi K, Koseki T, Sekine H, and Motohashi H. Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A. J Biochem 165: 323–334, 2019 PubMed

Durán RV, MacKenzie ED, Boulahbel H, Frezza C, Heiserich L, Tardito S, Bussolati O, Rocha S, Hall MN, and Gottlieb E. HIF-independent role of prolyl hydroxylases in the cellular response to amino acids. Oncogene 32: 4549–4556, 2013 PubMed PMC

Dvořák A, Zelenka J, Smolková K, Vítek L, and Ježek P. Background levels of neomorphic 2-hydroxyglutarate facilitate proliferation of primary fibroblasts. Physiol Res 66: 293–304, 2017 PubMed

Engqvist M, Drincovich MF, Flugge UI, and Maurino VG. Two D-2-hydroxy-acid dehydrogenases in Arabidopsis thaliana with catalytic capacities to participate in the last reactions of the methylglyoxal and b-oxidation pathways. J Biol Chem 284: 25026–25037, 2009 PubMed PMC

Engqvist MK, Esser C, Maier A, Lercher MJ, and Maurino VG. Mitochondrial 2-hydroxyglutarate metabolism. Mitochondrion 19B: 275–281, 2014 PubMed

Fack F, Tardito S, Hochart G, Oudin A, Zheng L, Fritah S, Golebiewska A, Nazarov PV, Bernard A, Hau AC, Keunen O, Leenders W, Lund-Johansen M, Stauber J, Gottlieb E, Bjerkvig R, and Niclou SP. Altered metabolic landscape in IDH-mutant gliomas affects phospholipid, energy, and oxidative stress pathways. EMBO Mol Med 9: 1681–1695, 2017 PubMed PMC

Fan J, Teng X, Liu L, Mattaini KR, Looper RE, Vander Heiden MG, and Rabinowitz JD. Human phosphoglycerate dehydrogenase produces the oncometabolite d-2-hydroxyglutarate. ACS Chem Biol 10: 510–516, 2015 PubMed PMC

Fan B, Mellinghoff IK, Wen PY, Lowery MA, Goyal L, Tap WD, Pandya SS, Manyak E, Jiang L, Liu G, Nimkar T, Gliser C, Prahl Judge M, Agresta S, Yang H, and Dai D.. Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors. Invest New Drugs 2019. [Epub ahead of print]; DOI: 10.1007/s10637-019-00771-x PubMed DOI PMC

Fathi AT, Nahed BV, Wander SA, Iafrate AJ, Borger DR, Hu R, Thabet A, Cahill DP, Perry AM, Joseph CP, Muzikansky A, and Chi AS. Elevation of urinary 2-hydroxyglutarate in IDH-mutant glioma. Oncologist 21: 214–219, 2016 PubMed PMC

Fathi AT, Sadrzadeh H, Comander AH, Higgins MJ, Bardia A, Perry A, Burke M, Silver R, Matulis CR, Straley KS, Yen KE, Agresta S, Kim H, Schenkein DP, and Borger DR. Isocitrate dehydrogenase 1 (IDH1) mutation in breast adenocarcinoma is associated with elevated levels of serum and urine 2-hydroxyglutarate. Oncologist 19: 602–607, 2014 PubMed PMC

Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ, Schifano E, Booth J, van Putten W, Skrabanek L, Campagne F, Mazumdar M, Greally JM, Valk PJ, Löwenberg B, Delwel R, and Melnick A. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17: 13–27, 2010 PubMed PMC

Fu X, Chin RM, Vergnes L, Hwang H, Deng G, Xing Y, Pai MY, Li S, Ta L, Fazlollahi F, Chen C, Prins RM, Teitell MA, Nathanson DA, Lai A, Faull KF, Jiang M, Clarke SG, Cloughesy TF, Graeber TG, Braas D, Christofk HR, Jung ME, Reue K, and Huang J. 2-Hydroxyglutarate inhibits ATP synthase and mTOR signaling. Cell Metab 22: 508–515, 2015 PubMed PMC

Gaal J, Burnichon N, Korpershoek E, Roncelin I, Bertherat J, Plouin PF, de Krijger RR, Gimenez-Roqueplo AP, and Dinjens WN. Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 95: 1274–1278, 2010 PubMed

Gagné LM, Boulay K, Topisirovic I, Huot MÉ, and Mallette FA. Oncogenic activities of IDH1/2 mutations: from epigenetics to cellular signaling. Trends Cell Biol 27: 738–752, 2017 PubMed

Galli S, Antico Arciuch VG, Poderoso C, Converso DP, Zhou Q, Bal de Kier Joffé E, Cadenas E, Boczkowski J, Carreras MC, and Poderoso JJ. Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria. PLoS One 3: e2379, 2008 PubMed PMC

Galluzzi L and Kroemer G. Potent immunosuppressive effects of the oncometabolite R-2-hydroxyglutarate. Oncoimmunology 7: e1528815, 2018 PubMed PMC

Garofalo O, Cox DW, and Bachelard HS. Brain levels of NADH and NAD+ under hypoxic and hypoglycaemic conditions in vitro. J Neurochem 51: 172–176, 1988 PubMed

Gelman SJ, Naser F, Mahieu NG, McKenzie LD, Dunn GP, Chheda MG, and Patti GJ. Consumption of NADPH for 2-HG synthesis increases pentose phosphate pathway flux and sensitizes cells to oxidative stress. Cell Rep 22: 512–522, 2018 PubMed PMC

Gonsalves WI, Ramakrishnan V, Hitosugi T, Ghosh T, Jevremovic D, Dutta T, Sakrikar D, Petterson XM, Wellik L, Kumar SK, and Nair KS. Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies. JCI Insight 3: 94543, 2018 PubMed PMC

Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, Sasaki M, Jin S, Schenkein DP, Su SM, Dang L, Fantin VR, and Mak TW. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 207: 339–344, 2010 PubMed PMC

Han SJ, Choi HS, Kim JI, Park JW, and Park KM. IDH2 deficiency increases the liver susceptibility to ischemia-reperfusion injury via increased mitochondrial oxidative injury. Redox Biol 14: 142–153, 2018 PubMed PMC

Han J, Jackson D, Holm J, Turner K, Ashcraft P, Wang X, Cook B, Arning E, Genta RM, Venuprasad K, Souza RF, Sweetman L, and Theiss AL. Elevated d-2-hydroxyglutarate during colitis drives progression to colorectal cancer. Proc Natl Acad Sci U S A 115: 1057–1062, 2018 PubMed PMC

Harding JJ, Lowery MA, Shih AH, Schvartzman JM, Hou S, Famulare C, Patel M, Roshal M, Do RK, Zehir A, You D, Selcuklu SD, Viale A, Tallman MS, Hyman DM, Reznik E, Finley LWS, Papaemmanuil E, Tosolini A, Frattini MG, MacBeth KJ, Liu G, Fan B, Choe S, Wu B, Janjigian YY, Mellinghoff IK, Diaz LA, Levine RL, Abou-Alfa GK, Stein EM, and Intlekofer AM. Isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition. Cancer Discov 8: 1540–1547, 2018 PubMed PMC

Hariharan VA, Denton TT, Paraszcszak S, McEvoy K, Jeitner TM, Krasnikov BF, and Cooper AJ. The enzymology of 2-hydroxyglutarate, 2-hydroxyglutaramate and 2-hydroxysuccinamate and their relationship to oncometabolites. Biology (Basel) 6: 24, 2017 PubMed PMC

Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W, Weller M, Herold-Mende C, Unterberg A, Jeuken JW, Wesseling P, Reifenberger G, and von Deimling A. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118: 469–474, 2009 PubMed

Hausinger RP. FeII/a-ketoglutarate-dependent hydroxylases and related enzymes. Crit Rev Biochem Mol Biol 39: 21–68, 2004 PubMed

Huang LE, Cohen AL, Colman H, Jensen RL, Fults DW, and Couldwell WT. IGFBP2 expression predicts IDH-mutant glioma patient survival. Oncotarget 8: 191–202, 2017 PubMed PMC

Intlekofer AM, Dematteo RG, Venneti S, Finley LW, Lu C, Judkins AR, Rustenburg AS, Grinaway PB, Chodera JD, Cross JR, and Thompson CB. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab 22: 304–311, 2015 PubMed PMC

Intlekofer AM, Shih AH, Wang B, Nazir A, Rustenburg AS, Albanese SK, Patel M, Famulare C, Correa FM, Takemoto N, Durani V, Liu H, Taylor J, Farnoud N, Papaemmanuil E, Cross JR, Tallman MS, Arcila ME, Roshal M, Petsko GA, Wu B, Choe S, Konteatis ZD, Biller SA, Chodera JD, Thompson CB, Levine RL, and Stein EM. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 559: 125–129, 2018 PubMed PMC

Intlekofer AM, Wang B, Liu H, Shah H, Carmona-Fontaine C, Rustenburg AS, Salah S, Gunner MR, Chodera JD, Cross JR, and Thompson CB. L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH. Nat Chem Biol 13: 494–500, 2017 PubMed PMC

Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, and Hayashi J. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320: 661–664, 2008 PubMed

Ježek P and Smolková K. The role of mitochondrial NADPH-dependent isocitrate dehydrogenase in cancer cells. Int J Cell Biol 2012: 273947, 2012 PubMed PMC

Jiang L, Shestov AA, Swain P, Yang C, Parker SJ, Wang QA, Terada LS, Adams ND, McCabe MT, Pietrak B, Schmidt S, Metallo CM, Dranka BP, Schwartz B, and DeBerardinis RJ. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532: 255–258, 2016 PubMed PMC

Jiang B, Zhao W, Shi M, Zhang J, Chen A, Ma H, Suleman M, Lin F, Zhou L, Wang J, Zhang Y, Liu M, Wen S, Ouyang C, Wang H, Huang X, Zhou H, and Li Q. IDH1 Arg-132 mutant promotes tumor formation through down-regulating p53. J Biol Chem 293: 9747–9758, 2018 PubMed PMC

Jo SH, Son MK, Koh HJ, Lee SM, Song IH, Kim YO, Lee YS, Jeong KS, Kim WB, Park JW, Song BJ, and Huh TL. Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase. J Biol Chem 276: 16168–16176, 2001 PubMed

Kaminska B, Czapski B, Guzik R, Król SK, and Gielniewski B.. Consequences of IDH1/2 mutations in gliomas and an assessment of inhibitors targeting mutated IDH proteins. Molecules 24, E968, 2019 PubMed PMC

Kanamori M, Maekawa M, Shibahara I, Saito R, Chonan M, Shimada M, Sonoda Y, Kumabe T, Watanabe M, Mano N, and Tominaga T. Rapid detection of mutation in isocitrate dehydrogenase 1 and 2 genes using mass spectrometry. Brain Tumor Pathol 35: 90–96, 2018 PubMed

Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Seo SI, Lee JY, Yoo NJ, and Lee SH. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer 125: 353–355, 2009 PubMed

Karpel-Massler G, Ishida CT, Bianchetti E, Zhang Y, Shu C, Tsujiuchi T, Banu MA, Garcia F, Roth KA, Bruce JN, Canoll P, and Siegelin MD. Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nat Commun 8: 1067, 2017 PubMed PMC

Kil IS, Kim SY, Lee SJ, and Park JW. Small interfering RNA-mediated silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase enhances the sensitivity of HeLa cells toward tumor necrosis factor-alpha and anticancer drugs. Free Radic Biol Med 43: 1197–1207, 2007 PubMed

Kil IS and Park JW. Regulation of mitochondrial NADP+-dependent isocitrate dehydrogenase activity by glutathionylation. J Biol Chem 280: 10846–10854, 2005 PubMed

Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, van der Meer R, Nguyen P, Savage J, Owens KM, Vassilopoulos A, Ozden O, Park SH, Singh KK, Abdulkadir SA, Spitz DR, Deng CX, and Gius D. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17: 41–52, 2010 PubMed PMC

Kim SJ, Yune TY, Han CT, Kim CY, Oh YJ, Markelonis GJ, and Oh TH. Mitochondrial isocitrate dehydrogenase protects human neuroblastoma SH-SY5Y cells against oxidative stress. J. Neurosci. Res 85: 139–152, 2007 PubMed

Kohanbash G, Carrera DA, Shrivastav S, Ahn BJ, Jahan N, Mazor T, Chheda ZS, Downey KM, Watchmaker PB, Beppler C, Warta R, Amankulor NA, Herold-Mende C, Costello JF, and Okada H. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J Clin Invest 127: 1425–1437, 2017 PubMed PMC

Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, Losman JA, Joensuu P, Bergmann U, Gross S, Travins J, Weiss S, Looper R, Ligon KL, Verhaak RG, Yan H, and Kaelin WG Jr. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484–488, 2012 PubMed PMC

Kranendijk M, Struys EA, Gibson KM, Wickenhagen WV, Abdenur JE, Buechner J, Christensen E, de Kremer RD, Errami A, Gissen P, Gradowska W, Hobson E, Islam L, Korman SH, Kurczynski T, Maranda B, Meli C, Rizzo C, Sansaricq C, Trefz FK, Webster R, Jakobs C, and Salomons GS. Evidence for genetic heterogenity in D-2-hydroxyglutaric aciduria. Hum Mutat 31: 279–283, 2010 PubMed

Kranendijk M, Struys EA, Salomons GS, Van der Knaap MS, and Jakobs C. Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis 35: 571–587, 2012 PubMed PMC

Laukka T, Myllykoski M, Looper RE, and Koivunen P. Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases. J Mol Biol 430, 3081–3092, 2018 PubMed

Lee P, and Colman RF. Thr373, Asp375, and Lys260 are in the coenzyme site of porcine NADP-dependent isocitrate dehydrogenase. Arch Biochem Biophys 450: 183–190, 2006 PubMed

Lee JH, Kim SY, Kil IS, and Park JW. Regulation of ionizing radiation-induced apoptosis by mitochondrial NADP+-dependent isocitrate dehydrogenase. J Biol Chem 282: 13385–13394, 2007 PubMed

Lemonnier F, Cairns RA, Inoue S, Li WY, Dupuy A, Broutin S, Martin N, Fataccioli V, Pelletier R, Wakeham A, Snow BE, de Leval L, Pujals A, Haioun C, Paci A, Tobin ER, Narayanaswamy R, Yen K, Jin S, Gaulard P, and Mak TW. The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development. Proc Natl Acad Sci U S A 113: 15084–15089, 2016 PubMed PMC

Levell JR, Caferro T, Chenail G, Dix I, Dooley J, Firestone B, Fortin PD, Giraldes J, Gould T, Growney JD, Jones MD, Kulathila R, Lin F, Liu G, Mueller A, van der Plas S, Slocum K, Smith T, Terranova R, Touré BB, Tyagi V, Wagner T, Xie X, Xu M, Yang FS, Zhou LX, Pagliarini R, and Cho YS. Optimization of 3-pyrimidin-4-yl-oxazolidin-2-ones as allosteric and mutant specific inhibitors of IDH1. ACS Med Chem Lett 8: 151–156, 2016 PubMed PMC

Li T, Cox CD, Ozer BH, Nguyen NT, Nguyen HN, Lai TJ, Li S, Liu F, Kornblum HI, Liau LM, Nghiemphu PL, Cloughesy TF, and Lai A. D-2-Hydroxyglutarate is necessary and sufficient for isocitrate dehydrogenase 1 mutant-induced MIR148A promoter methylation. Mol Cancer Res 16: 947–960, 2018 PubMed PMC

Lin AP, Abbas S, Kim SW, Ortega M, Bouamar H, Escobedo Y, Varadarajan P, Qin Y, Sudderth J, Schulz E, Deutsch A, Mohan S, Ulz P, Neumeister P, Rakheja D, Gao X, Hinck A, Weintraub ST, DeBerardinis RJ, Sill H, Dahia PL, and Aguiar RC. D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. Nat Commun 6: 7768, 2015 PubMed PMC

Linos K and Tafe LJ. Isocitrate dehydrogenase 1 mutations in melanoma frequently co-occur with NRAS mutations. Histopathology 73, 963–968, 2018 PubMed

Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, and Vander Heiden MG. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 43: 869–874, 2011 PubMed PMC

Longuespée R, Wefers AK, De Vita E, Miller AK, Reuss DE, Wick W, Herold-Mende C, Kriegsmann M, Schirmacher P, von Deimling A, and Pusch S. Rapid detection of 2-hydroxyglutarate in frozen sections of IDH mutant tumors by MALDI-TOF mass spectrometry. Acta Neuropathol Commun 6: 21, 2018 PubMed PMC

Losman JA and Kaelin WG Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 27: 836–852, 2013 PubMed PMC

Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C, Cowley GS, Root DE, Ebert BL, and Kaelin WG Jr. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339: 1621–1625, 2013 PubMed PMC

Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O'’Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, and Thompson CB. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483: 474–478, 2012 PubMed PMC

Lucca LE and Hafler DA. Resisting fatal attraction: a glioma oncometabolite prevents CD8+ T cell recruitment. J Clin Invest 127: 1218–1220, 2017 PubMed PMC

Ma R and Yun CH. Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2. Biochem Biophys Res Commun 503: 2912–2917, 2018 PubMed

Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Eldred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, McMichael JF, Meyer RJ, Schindler JK, Pohl CS, Wallis JW, Shi X, Lin L, Schmidt H, Tang Y, Haipek C, Wiechert ME, Ivy JV, Kalicki J, Elliott G, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson MA, Baty J, Heath S, Shannon WD, Nagarajan R, Link DC, Walter MJ, Graubert TA, DiPersio JF, Wilson RK, and Ley TJ. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361: 1058–1066, 2009 PubMed PMC

Markolovic S, Leissing TM, Chowdhury R, Wilkins SE, Lu X, and Schofield CJ. Structure-function relationships of human JmjC oxygenases-demethylases versus hydroxylases. Curr Opin Struct Biol 41: 62–72, 2016 PubMed

Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, and Dong C. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31: 787–798, 2009 PubMed PMC

Matre P, Velez J, Jacamo R, Qi Y, Su X, Cai T, Chan SM, Lodi A, Sweeney SR, Ma H, Davis RE, Baran N, Haferlach T, Su X, Flores ER, Gonzalez D, Konoplev S, Samudio I, DiNardo C, Majeti R, Schimmer AD, Li W, Wang T, Tiziani S, and Konopleva M. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes. Oncotarget 7: 79722–79735, 2016 PubMed PMC

Matsunaga H, Futakuchi-Tsuchida A, Takahashi M, Ishikawa T, Tsuji M, and Ando O. IDH1 and IDH2 have critical roles in 2-hydroxyglutarate production in D-2-hydroxyglutarate dehydrogenase depleted cells. Biochem Biophys Res Commun 423: 553–556, 2012 PubMed

Matteo AD, Wells GA, Luna LA, Grunseth AJ, Zagnitko O, Scott DA, Hoang A, Luthra A, Swairjo MA, Schiffer JM, and Sohl CD. Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants. Biochem J 475: 3221–3238, 2018 PubMed PMC

Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, and Stephanopoulos G. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481: 380–384, 2011 PubMed PMC

Miller JJ, Shih HA, Andronesi OC, and Cahill DP. Isocitrate dehydrogenase-mutant glioma: evolving clinical and therapeutic implications. Cancer 123: 4535–4546, 2017 PubMed

Minich T, Yokota S, and Dringen R. Cytosolic and mitochondrial isoforms of NADP+-dependent isocitrate dehydrogenases are expressed in cultured rat neurons, astrocytes, oligodendrocytes and microglial cells. J Neurochem 86: 605–614, 2003 PubMed

Mishra P, Tang W, and Ambs S. ADHFE1 is a MYC-linked oncogene that induces metabolic reprogramming and cellular de-differentiation in breast cancer. Mol Cell Oncol 5: e1432260, 2018 PubMed PMC

Mishra P, Tang W, Putluri V, Dorsey TH, Jin F, Wang F, Zhu D, Amable L, Deng T, Zhang S, Killian JK, Wang Y, Minas TZ, Yfantis HG, Lee DH, Sreekumar A, Bustin M, Liu W, Putluri N, and Ambs S. ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming. J Clin Invest 128: 323–340, 2018 PubMed PMC

Molenaar RJ, Radivoyevitch T, Nagata Y, Khurshed M, Przychodzen B, Makishima H, Xu M, Bleeker FE, Wilmink JW, Carraway HE, Mukherjee S, Sekeres MA, van Noorden CJF, and Maciejewski JP. IDH1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors. Clin Cancer Res 24: 1705–1715, 2018 PubMed PMC

Mullen AR, Hu Z, Shi X, Jiang L, Boroughs LK, Kovacs Z, Boriack R, Rakheja D, Sullivan LB, Linehan WM, Chandel NS, and DeBerardinis RJ. Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep 7: 1679–1690, 2014 PubMed PMC

Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, and DeBerardinis RJ. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481: 385, 2011 PubMed PMC

Nadtochiy SM, Schafer X, Fu D, Nehrke K, Munger J, and Brookes PS. Acidic pH is a metabolic switch for 2-hydroxyglutarate generation and signaling. J Biol Chem 291: 20188–20197, 2016 PubMed PMC

Nassereddine S, Lap CJ, and Tabbara IA. Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy. Onco Targets Ther 12: 303–308, 2019 PubMed PMC

Ni M, Solmonson A, Pan C, Yang C, Li D, Notzon A, Cai L, Guevara G, Zacharias LG, Faubert B, Vu HS, Jiang L, Ko B, Morales NM, Pei J, Vale G, Rakheja D, Grishin NV, McDonald JG, Gotway GK, McNutt MC, Pascual JM, and DeBerardinis RJ. Functional assessment of lipoyltransferase-1 deficiency in cells, mice, and humans. Cell Rep 27: 1376–1386, 2019 PubMed PMC

Ohba S, Mukherjee J, Johannessen TC, Mancini A, Chow TT, Wood M, Jones L, Mazor T, Marshall RE, Viswanath P, Walsh KM, Perry A, Bell RJ, Phillips JJ, Costello JF, Ronen SM, and Pieper RO. Mutant IDH1 expression drives TERT promoter reactivation as part of the cellular transformation process. Cancer Res 76: 6680–6689, 2016 PubMed PMC

Ohka F, Ito M, Ranjit M, Senga T, Motomura A, Motomura K, Saito K, Kato K, Kato Y, Wakabayashi T, Soga T, and Natsume A. Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. Tumour Biol 35: 5911–5920, 2014 PubMed

Okoye-Okafor UC, Bartholdy B, Cartier J, Gao EN, Pietrak B, Rendina AR, Rominger C, Quinn C, Smallwood A, Wiggall KJ, Reif AJ, Schmidt SJ, Qi H, Zhao H, Joberty G, Faelth-Savitski M, Bantscheff M, Drewes G, Duraiswami C, Brady P, Groy A, Narayanagari SR, Antony-Debre I, Mitchell K, Wang HR, Kao YR, Christopeit M, Carvajal L, Barreyro L, Paietta E, Makishima H, Will B, Concha N, Adams ND, Schwartz B, McCabe MT, Maciejewski J, Verma A, and Steidl U. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nat Chem Biol 11: 878–886, 2015 PubMed PMC

Oldham WM, Clish CB, Yang Y, and Loscalzo J. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab 22: 291–303, 2015 PubMed PMC

Pan JS, Hong MZ, and Ren JL. Reactive oxygen species: a double-edged sword in oncogenesis. World J Gastroenterol 15: 1702–1707, 2009 PubMed PMC

Panieri E and Santoro MM. ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell Death Dis 7: e2253, 2016 PubMed PMC

Park GHJ, Yang SH, and Baek HM. 900MHz 1H-/13C-NMR analysis of 2-hydroxyglutarate and other brain metabolites in human brain tumor tissue extracts. PLoS One 13: e0203379, 2018 PubMed PMC

Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr., Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, and Kinzler KW.. An integrated genomic analysis of human glioblastoma multiforme. Science 321: 1807–1812, 2008 PubMed PMC

Philip B, Yu DX, Silvis MR, Shin CH, Robinson JP, Robinson GL, Welker AE, Angel SN, Tripp SR, Sonnen JA, VanBrocklin MW, Gibbons RJ, Looper RE, Colman H, and Holmen SL. Mutant IDH1 promotes glioma formation in vivo. Cell Rep 23: 1553–1564, 2018 PubMed PMC

Pop A, Struys EA, Jansen EEW, Fernandez MR, Kanhai WA, van Dooren SJM, Ozturk S, van Oostendorp J, Lennertz P, Kranendijk M, van der Knaap MS, Gibson KM, van Schaftingen E, and Salomons GS. D-2-Hydroxyglutaric aciduria type I: functional analysis of D2HGDH missense variants. Hum Mutat 40: 975–982, 2019 PubMed PMC

Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, Cianchetta G, Cai Z, Zhou D, Cui D, Chen P, Straley K, Tobin E, Wang F, David MD, Penard-Lacronique V, Quivoron C, Saada V, de Botton S, Gross S, Dang L, Yang H, Utley L, Chen Y, Kim H, Jin S, Gu Z, Yao G, Luo Z, Lv X, Fang C, Yan L, Olaharski A, Silverman L, Biller S, Su SM, and Yen K. Discovery of AG-120 (ivosidenib): a first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med Chem Lett 9: 300–305, 2018 PubMed PMC

Popovici-Muller J, Saunders JO, Salituro FG, Travins JM, Yan S, Zhao F, Gross S, Dang L, Yen KE, Yang H, Straley KS, Jin S, Kunii K, Fantin VR, Zhang S, Pan Q, Shi D, Biller SA, and Su SM. Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo. ACS Med Chem Lett 3: 850–855, 2012 PubMed PMC

Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, and Sabatini DM. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476: 346–350, 2011 PubMed PMC

Qi F, Chen X, and Beard DA. Detailed kinetics and regulation of mammalian NAD-linked isocitrate dehydrogenase. Biochim Biophys Acta 1784: 1641–1651, 2008 PubMed PMC

Raffel S, Falcone M, Kneisel N, Hansson J, Wang W, Lutz C, Bullinger L, Poschet G, Nonnenmacher Y, Barnert A, Bahr C, Zeisberger P, Przybylla A, Sohn M, Tönjes M, Erez A, Adler L, Jensen P, Scholl C, Fröhling S, Cocciardi S, Wuchter P, Thiede C, Flörcken A, Westermann J, Ehninger G, Lichter P, Hiller K, Hell R, Herrmann C, Ho AD, Krijgsveld J, Radlwimmer B, and Trumpp A. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551: 384–388, 2017 PubMed

Raineri S and Mellor J. IDH1: linking metabolism and epigenetics. Front Genet 9: 493, 2018 PubMed PMC

Reitman ZJ, Duncan CG, Poteet E, Winters A, Yan LJ, Gooden DM, Spasojevic I, Boros LG, Yang SH, and Yan H. Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. J Biol Chem 289: 23318–23328, 2014 PubMed PMC

Rifaï K, Idrissou M, Penault-Llorca F, Bignon YJ, and Bernard-Gallon D. Breaking down the contradictory roles of histone deacetylase SIRT1 in human breast cancer. Cancers (Basel) 10: pii:, 2018 PubMed PMC

Ryan DG, Murphy MP, Frezza C, Prag HA, Chouchani ET, O'Neill LA, and Mills EL. Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nat Metab 1: 16–33, 2019 PubMed PMC

Rzem R, Vincent MF, Van Schaftingen E, and Veiga-da-Cunha M. L-2-hydroxyglutaric aciduria, a defect of metabolite repair. J Inherit Metab Dis 30: 681–689, 2007 PubMed

Sajnani K, Islam F, Smith RA, Gopalan V, and Lam AK. Genetic alterations in Krebs cycle and its impact on cancer pathogenesis. Biochimie 135: 164–172, 2017 PubMed

Salamanca-Cardona L, Shah H, Poot AJ, Correa FM, Di Gialleonardo V, Lui H, Miloushev VZ, Granlund KL, Tee SS, Cross JR, Thompson CB, and Keshari KR. In vivo imaging of glutamine metabolism to the oncometabolite 2-hydroxyglutarate in IDH1/2 mutant tumors. Cell Metab 26: 830–841, 2017 PubMed PMC

Samant SA, Zhang HJ, Hong Z, Pillai VB, Sundaresan NR, Wolfgeher D, Archer SL, Chan DC, and Gupta MP. SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 34: 807–819, 2014 PubMed PMC

Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, Chio II, Cairns RA, McCracken S, Wakeham A, Haight J, Ten AY, Snow B, Ueda T, Inoue S, Yamamoto K, Ko M, Rao A, Yen KE, Su SM, and Mak TW. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev 26: 2038–2049, 2012 PubMed PMC

Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brüstle A, Harris IS, Holmes R, Wakeham A, Haight J, You-Ten A, Li WY, Schalm S, Su SM, Virtanen C, Reifenberger G, Ohashi PS, Barber DL, Figueroa ME, Melnick A, Zúñiga-Pflücker JC, and Mak TW. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488: 656–659, 2012 PubMed PMC

Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, Tsukamoto T, Rojas CJ, Slusher BS, Rabinowitz JD, Dang CV, and Riggins GJ. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res 70: 8981–8987, 2010 PubMed PMC

Sequist LV, Heist RS, Shaw AT, Fidias P, Rosovsky R, Temel JS, Lennes IT, Digumarthy S, Waltman BA, Bast E, Tammireddy S, Morrissey L, Muzikansky A, Goldberg SB, Gainor J, Channick CL, Wain JC, Gaissert H, Donahue DM, Muniappan A, Wright C, Willers H, Mathisen DJ, Choi NC, Baselga J, Lynch TJ, Ellisen LW, Mino-Kenudson M, Lanuti M, Borger DR, Iafrate AJ, Engelman JA, and Dias-Santagata D. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol 22: 2616–2624, 2011 PubMed PMC

Shelar S, Shim EH, Brinkley GJ, Kundu A, Carobbio F, Poston T, Tan J, Parekh V, Benson D, Crossman DK, Buckhaults PJ, Rakheja D, Kirkman R, Sato Y, Ogawa S, Dutta S, Velu SE, Emberley E, Pan A, Chen J, Huang T, Absher D, Becker A, Kunick C, and Sudarshan S. Biochemical and epigenetic insights into L-2-hydroxyglutarate, a potential therapeutic target in renal cancer. Clin Cancer Res 24: 6433–6446, 2018 PubMed PMC

Shen X, Voets NL, Larkin SJ, de Pennington N, Plaha P, Stacey R, McCullagh JSO, Schofield CJ, Clare S, Jezzard P, Cadoux-Hudson T, Ansorge O, and Emir UE. A noninvasive comparison study between human gliomas with IDH1 and IDH2 mutations by MR spectroscopy. Metabolites 9: E35, 2019 PubMed PMC

Shi J, Zuo H, Ni L, Xia L, Zhao L, Gong M, Nie D, Gong P, Cui D, Shi W, and Chen J. An IDH1 mutation inhibits growth of glioma cells via GSH depletion and ROS generation. Neurol Sci 35: 839–845, 2014 PubMed

Shin SW, Kil IS, and Park JW. Silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase by small interfering RNA enhances heat shock-induced apoptosis. Biochem Biophys Res Commun 366: 1012–1018, 2008 PubMed

Sica V, Bravo-San Pedro JM, Izzo V, Pol J, Pierredon S, Enot D, Durand S, Bossut N, Chery A, Souquere S, Pierron G, Vartholomaiou E, Zamzami N, Soussi T, Sauvat A, Mondragón L, Kepp O, Galluzzi L, Martinou JC, Hess-Stumpp H, Ziegelbauer K, Kroemer G, and Maiuri MC. Lethal poisoning of cancer cells by respiratory chain inhibition plus dimethyl α-ketoglutarate. Cell Rep 27: 820–834, 2019 PubMed

Simic Z, Weiwad M, Schierhorn A, Steegborn C, and Schutkowski M. The Ɛ-amino group of protein lysine residues is highly susceptible to nonenzymatic acylation by several physiological Acyl-CoA thioesters. Chembiochem 16: 2337–2347, 2015 PubMed

Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, and Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science 314: 268–274, 2006 PubMed

Smolková K, Dvořák A, Zelenka J, Vítek L, and Ježek P. Reductive carboxylation and 2-hydroxyglutarate formation by wild-type IDH2 in breast carcinoma cells. Int J Biochem Cell Biol 65: 125–133, 2015 PubMed

Smolková K, Plecitá-Hlavatá L, Bellance N, Benard G, Rossignol R, and Ježek P. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell Biol 43: 950–968, 2011 PubMed

Smolková K, Špačková J, Dvořák A, Vítek L, and Ježek P. Mitochondrial 2HG production as a function of IDH2 and HOT in breast cancer cells. Biochim Biophys Acta 1859 (Suppl 1): e105, 2018

Song Y and Yang JM. Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer. Biochem Biophys Res Commun 493: 1–8, 2017 PubMed

Soundar S, Danek BL, and Colman RF. Identification by mutagenesis of arginines in the substrate binding site of the porcine NADP-dependent isocitrate dehydrogenase. J Biol Chem 275: 5606–5612, 2000 PubMed

Stein EM, DiNardo CD, Fathi AT, Pollyea DA, Stone RM, Altman JK, Roboz GJ, Patel MR, Collins R, Flinn IW, Sekeres MA, Stein AS, Kantarjian HM, Levine RL, Vyas P, MacBeth KJ, Tosolini A, VanOostendorp J, Xu Q, Gupta I, Lila T, Risueno A, Yen KE, Wu B, Attar EC, Tallman MS, and de Botton S. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood 133: 676–687, 2019 PubMed PMC

Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, DeAngelo DJ, Levine RL, Flinn IW, Kantarjian HM, Collins R, Patel MR, Frankel AE, Stein A, Sekeres MA, Swords RT, Medeiros BC, Willekens C, Vyas P, Tosolini A, Xu Q, Knight RD, Yen KE, Agresta S, de Botton S, and Tallman MS. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130: 722–731, 2017 PubMed PMC

Struys EA, Salomons GS, Achouri Y, Van Schaftingen E, Grosso S, Craigen WJ, Verhoeven NM, and Jakobs C. Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am J Hum Genet 76: 358–360, 2005 PubMed PMC

Struys EA, Verhoeven NM, Ten Brink HJ, Wickenhagen WV, Gibson KM, and Jakobs C. Kinetic characterization of human hydroxyacid–oxoacid transhydrogenase: relevance to D-2-hydroxyglutaric and g-hydroxybutyric acidurias. J Inherit Metab Dis 28: 921–930, 2005 PubMed

Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, Liu Y, Sundaram RK, Hegan DC, Fons NR, Breuer GA, Song Y, Mishra-Gorur K, De Feyter HM, de Graaf RA, Surovtseva YV, Kachman M, Halene S, Günel M, Glazer PM, and Bindra RS. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med 9: 2463, 2017 PubMed PMC

Sullivan LB, Gui DY, and Heiden MGV. Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat Rev Cancer 16: 680–693, 2016 PubMed

Tafti M, Petit B, Chollet D, Neidhart E, de Bilbao F, Kiss JZ, Wood PA, and Franken P. Deficiency in short-chain fatty acid -oxidation affects theta oscillations during sleep. Nat Genet 34: 320–325, 2003 PubMed

Tang X, Lin CC, Spasojevic I, Iversen ES, Chi JT, and Marks JR. A joint analysis of metabolomics and genetics of breast cancer. Breast Cancer Res 16: 415, 2014 PubMed PMC

Tarhonskaya H, Rydzik AM, Leung IKH, Loik ND, Chan MC, Kawamura A, McCullagh JSO, Claridge TDW, Flashman E, and Schofield CJ. Non-enzymatic chemistry enables 2-hydroxyglutarate mediated activation of 2-oxoglutarate oxygenases. Nat Commun 5: 3423, 2014 PubMed PMC

Terunuma A, Putluri N, Mishra P, Mathé EA, Dorsey TH, Yi M, Wallace TA, Issaq HJ, Zhou M, Killian JK, Stevenson HS, Karoly ED, Chan K, Samanta S, Prieto D, Hsu TY, Kurley SJ, Putluri V, Sonavane R, Edelman DC, Wulff J, Starks AM, Yang Y, Kittles RA, Yfantis HG, Lee DH, Ioffe OB, Schiff R, Stephens RM, Meltzer PS, Veenstra TD, Westbrook TF, Sreekumar A, and Ambs S. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest 124: 398–412, 2014 PubMed PMC

Torrens-Mas M, Hernández-López R, Oliver J, Roca P, and Sastre-Serra J. Sirtuin 3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer. J Cell Physiol 233: 6067–6076, 2018 PubMed

Torrens-Mas M, Hernández-López R, Pons DG, Roca P, Oliver J, and Sastre-Serra J. Sirtuin 3 silencing impairs mitochondrial biogenesis and metabolism in colon cancer cells. Am J Physiol Cell Physiol 317: C398–C404, 2019 PubMed

Torrens-Mas M, Pons DG, Sastre-Serra J, Oliver J, and Roca P. SIRT3 silencing sensitizes breast cancer cells to cytotoxic treatments through an increment in ROS production. J Cell Biochem 118: 397–406, 2017 PubMed

Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT, Veliça P, You J, Chia GS, Sim J, Doedens A, Abelanet A, Evans CE, Griffiths JR, Poellinger L, Goldrath AW, and Johnson RS. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540: 236–241, 2016 PubMed PMC

Upadhyay VA, Brunner AM, and Fathi AT. Isocitrate dehydrogenase (IDH) inhibition as treatment of myeloid malignancies: progress and future directions. Pharmacol Ther 177: 123–128, 2017 PubMed

Vassilopoulos A, Pennington JD, Andresson T, Rees DM, Bosley AD, Fearnley IM, Ham A, Flynn CR, Hill S, Rose KL, Kim HS, Deng CX, Walker JE, and Gius D. SIRT3 deacetylates ATP synthase F1 complex proteins in response to nutrient- and exercise-induced stress. Antioxid Redox Signal 21: 551–564, 2014 PubMed PMC

Viswanath P, Radoul M, Izquierdo-Garcia JL, Luchman HA, Gregory Cairncross J, Pieper RO, Phillips JJ, and Ronen SM. Mutant IDH1 gliomas downregulate phosphocholine and phosphoethanolamine synthesis in a 2-hydroxyglutarate-dependent manner. Cancer Metab 6: 3, 2018 PubMed PMC

Vitale I, Manic G, Coussens LM, Kroemer G, and Galluzzi L. Macrophages and metabolism in the tumor microenvironment. Cell Metab 30: 36–50, 2019 PubMed

Wagner GR and Payne RM. Widespread and enzyme-independent Nɛ-acetylation and Nɛ-succinylation of proteins in the chemical conditions of the mitochondrial matrix. J Biol Chem 288: 29036–29045, 2013 PubMed PMC

Waitkus MS, Pirozzi CJ, Moure CJ, Diplas BH, Hansen LJ, Carpenter AB, Yang R, Wang Z, Ingram BO, Karoly ED, Mohney RP, Spasojevic I, McLendon RE, Friedman HS, He Y, Bigner DD, and Yan H. Adaptive evolution of the GDH2 allosteric domain promotes gliomagenesis by resolving IDH1R132H-induced metabolic liabilities. Cancer Res 78: 36–50, 2018 PubMed PMC

Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S, and Yen KE. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340: 622–626, 2013 PubMed

Ward PS, Cross JR, Lu C, Weigert O, Abel-Wahab O, Levine RL, Weinstock DM, Sharp KA, and Thompson CB. Identification of additional IDH mutations associated with oncometabolite R(-)-2-hydroxyglutarate production. Oncogene 31: 2491–2498, 2012 PubMed PMC

Ward PS, Lu C, Cross JR, Abdel-Wahab O, Levine RL, Schwartz GK, and Thompson CB. The potential for isocitrate dehydrogenase mutations to produce 2-hydroxyglutarate depends on allele specificity and subcellular compartmentalization. J Biol Chem 288: 3804–3815, 2013 PubMed PMC

Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, and Thompson CB. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225–234, 2010 PubMed PMC

Wise DR, Ward PS, Shay JES, Cross JR, Gruber JJ, and Sachdeva UM. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A 108: 19611–19616, 2011 PubMed PMC

Xie X, Baird D, Bowen K, Capka V, Chen J, Chenail G, Cho Y, Dooley J, Farsidjani A, Fortin P, Kohls D, Kulathila R, Lin F, McKay D, Rodrigues L, Sage D, Touré BB, van der Plas S, Wright K, Xu M, Yin H, Levell J, and Pagliarini RA. Allosteric mutant IDH1 inhibitors reveal mechanisms for IDH1 mutant and isoform selectivity. Structure 25: 506–513, 2017 PubMed

Xu T, Stewart KM, Wang X, Liu K, Xie M, Ryu JK, Li K, Ma T, Wang H, Ni L, Zhu S, Cao N, Zhu D, Zhang Y, Akassoglou K, Dong C, Driggers EM, and Ding S. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature 548: 228–233, 2017 PubMed PMC

Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, and Xiong Y. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of a-ketoglutaratedependent dioxygenases. Cancer Cell 19: 17–30, 2011 PubMed PMC

Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, and Ding J. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem 279: 33946–33957, 2004 PubMed

Yan B, Hu Y, Ma T, and Wang Y. IDH1 mutation promotes lung cancer cell proliferation through methylation of Fibulin-5. Open Biol 8: 180086, 2018 PubMed PMC

Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, and Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl J Med 360: 765–773, 2009 PubMed PMC

Yang B, Zhong C, Peng Y, Lai Z, and Ding J. Molecular mechanisms of “off-on switch” of activities of human IDH1 by tumor-associated mutation R132H. Cell Res 20: 1188–1200, 2010 PubMed

Yang Z, Jiang B, Wang Y, Ni H, Zhang J, Xia J, Shi M, Hung LM, Ruan J, Mak TW, Li Q, and Han J. 2-HG inhibits necroptosis by stimulating DNMT1-dependent hypermethylation of the RIP3 promoter. Cell Rep 19: 1846–1857, 2017 PubMed

Ye D, Guan KL, and Xiong Y. Metabolism, activity, and targeting of d and l-2-hydroxyglutarates. Trends in Cancer 4: 151–165, 2018 PubMed PMC

Yu W, Denu RA, Krautkramer KA, Grindle KM, Yang DT, Asimakopoulos F, Hematti P, and Denu JM. Loss of SIRT3 provides growth advantage for B cell malignancies. J Biol Chem 291: 3268–3279, 2016 PubMed PMC

Yu W, Dittenhafer-Reed KE, and Denu JM. SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status. J Biol Chem 287: 14078–14086, 2012 PubMed PMC

Yuneva M. Finding an “Achilles' heel” of cancer. Cell Cycle 7: 2083–2089, 2008 PubMed

Zhang L, Qi M, Feng T, Hu J, Wang L, Li X, Gao W, Liu H, Jiao M, Wu Z, Bai X, Bie Y, Liu L, and Han B. IDH1R132H promotes malignant transformation of benign prostatic epithelium by dysregulating microRNAs: involvement of IGF1R-AKT/STAT3 signaling pathway. Neoplasia 20: 207–217, 2018 PubMed PMC

Zhang Y, Wei H, Tang K, Lin D, Zhang C, Mi Y, Wang L, Wang C, Wang M, and Wang J. Mutation analysis of isocitrate dehydrogenase in acute lymphoblastic leukemia. Genet Test Mol Biomarkers 16: 991–995, 2012 PubMed PMC

Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, Yu W, Li Z, Gong L, Peng Y, Ding J, Lei Q, Guan KL, and Xiong Y. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324: 261–265, 2009 PubMed PMC

Zhou L, Wang F, Sun R, Chen X, Zhang M, Xu Q, Wang Y, Wang S, Xiong Y, Guan KL, Yang P, Yu H, and Ye D. SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense. EMBO Rep 17: 811–822, 2016 PubMed PMC

Zou X, Zhu Y, Park SH, Liu G, O'Brien J, Jiang H, and Gius D. SIRT3-mediated dimerization of IDH2 directs cancer cell metabolism and tumor growth. Cancer Res 77: 3990–3999, 2017 PubMed PMC

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