L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH
Open accessAbstract
The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D-R- or L-S- enantiomer, each of which inhibits α-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase (IDH) produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via 'promiscuous' reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
L-2-HG accumulation in an acidic pH environment results in HIF-1α stabilization in normoxia.
“In addition, L-2-HG accumulation in an acidic pH environment has been reported to result in HIF-1α stabilization in normoxia91 (Fig. 4).”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [91]
Malonate is protective when added at reperfusion.
“Malonate itself was also protective when added at reperfusion152,153.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [152]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules
Cornell, W. D., Cieplak, P., Bayly, C. I., Gould, I. R., Merz, K. M., Ferguson, D. M., Spellmeyer, D. C., Fox, T., Caldwell, J. W., & Kollman, P. A. (1995) · Journal of the American Chemical Society · doi:10.1021/ja00124a002 · Cited by 13,111 · see citing works
Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T., Repasky, M. P., Knoll, E. H., Shelley, M., Perry, J. K., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm0306430 · Cited by 10,057 · see citing works
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926 · see citing works
Self-citationHalgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L., Pollard, W. T., & Banks, J. L. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm030644s · Cited by 5,280 · see citing works
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154 · see citing works
Self-citationJakalian, A., Jack, D. B., & Bayly, C. I. (2002) · Journal of Computational Chemistry · doi:10.1002/jcc.10128 · Cited by 3,428 · see citing works
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875 · see citing works
Self-citationFigueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766 · see citing works
Self-citationShelley, J. C., Cholleti, A., Frye, L. L., Greenwood, J. R., Timlin, M. R., & Uchimaya, M. (2007) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-007-9133-z · Cited by 2,091 · see citing works
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068 · see citing works
Ward, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.020 · Cited by 2,020 · see citing works
Self-citationWise, D. R., DeBerardinis, R. J., Mancuso, A., Sayed, N., Zhang, X.-Y., Pfeiffer, H. K., Nissim, I., Daikhin, E., Yudkoff, M., McMahon, S. B., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810199105 · Cited by 2,001 · see citing works
Self-citationIDH mutation impairs histone demethylation and results in a block to cell differentiation
Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C. R., Khanin, R., Figueroa, M. E., Melnick, A., et al. (2012) · Nature · doi:10.1038/nature10860 · Cited by 1,985 · see citing works
Self-citationReductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791 · see citing works
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., et al. (2011) · Nature · doi:10.1038/nature10350 · Cited by 1,683 · see citing works
Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method
Jakalian, A., Bush, B. L., Jack, D. B., & Bayly, C. I. (2000) · Journal of Computational Chemistry · doi:10.1002/(sici)1096-987x(20000130)21:2 · Cited by 1,681 · see citing works
Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
Locasale, J. W., Grassian, A. R., Melman, T., Lyssiotis, C. A., Mattaini, K. R., Bass, A. J., Heffron, G., Metallo, C. M., Muranen, T., Sharfi, H., et al. (2011) · Nature Genetics · doi:10.1038/ng.890 · Cited by 1,120 · see citing works
Glioma-Derived Mutations in <i>IDH1</i> Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., et al. (2009) · Science · doi:10.1126/science.1170944 · Cited by 1,119 · see citing works
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases
Chowdhury, R., Yeoh, K. K., Tian, Y., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K. H., Li, X. S., Woon, E. C. Y., Yang, M., et al. (2011) · The EMBO Reports · doi:10.1038/embor.2011.43 · Cited by 1,035 · see citing works
Wise, D. R., Ward, P. S., Shay, J. E. S., Cross, J. R., Gruber, J. J., Sachdeva, U. M., Platt, J. M., DeMatteo, R. G., Simon, M. C., & Thompson, C. B. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117773108 · Cited by 975 · see citing works
Self-citationThe role of oxygen availability in embryonic development and stem cell function
Simon, M. C., & Keith, B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2354 · Cited by 966 · see citing works
SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1α Destabilization
Finley, L. W. S., Carracedo, A., Lee, J., Souza, A., Egia, A., Zhang, J., Teruya-Feldstein, J., Moreira, P. I., Cardoso, S. M., Clish, C. B., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.02.014 · Cited by 782 · see citing works
Chiche, J., Ilc, K., Laferrière, J., Trottier, E., Dayan, F., Mazure, N. M., Brahimi-Horn, M. C., & Pouysségur, J. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-2470 · Cited by 751 · see citing works
Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation
Koivunen, P., Lee, S., Duncan, C. G., Lopez, G., Lu, G., Ramkissoon, S., Losman, J. A., Joensuu, P., Bergmann, U., Gross, S., et al. (2012) · Nature · doi:10.1038/nature10898 · Cited by 727 · see citing works
What a difference a hydroxyl makes: mutant IDH, (<i>R</i>)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570 · see citing works
Hypoxia Induces Production of L-2-Hydroxyglutarate
Intlekofer, A. M., Dematteo, R. G., Venneti, S., Finley, L. W. S., Lu, C., Judkins, A. R., Rustenburg, A. S., Grinaway, P. B., Chodera, J. D., Cross, J. R., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.023 · Cited by 513 · see citing works
Self-citationIDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics
Sasaki, M., Knobbe, C. B., Munger, J. C., Lind, E. F., Brenner, D., Brüstle, A., Harris, I. S., Holmes, R., Wakeham, A., Haight, J., et al. (2012) · Nature · doi:10.1038/nature11323 · Cited by 513 · see citing works
On the calculation of pKas in proteins
Yang, A., Gunner, M. R., Sampogna, R. V., Sharp, K. A., & Honig, B. H. (1993) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.340150304 · Cited by 508 · see citing works
Self-citationRefinement of protein conformations using a macromolecular energy minimization procedure
Levitt, M., & Lifson, S. (1969) · Journal of Molecular Biology · doi:10.1016/0022-2836(69)90421-5 · Cited by 466 · see citing works
Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer
Saha, S. K., Parachoniak, C. A., Ghanta, K. S., Fitamant, J., Ross, K. N., Najem, M. S., Gurumurthy, S., Akbay, E. A., Sia, D., Cornellà, H., et al. (2014) · Nature · doi:10.1038/nature13441 · Cited by 460 · see citing works
MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis
Terunuma, A., Putluri, N., Mishra, P., Mathé, E. A., Dorsey, T. H., Yi, M., Wallace, T. A., Issaq, H. J., Zhou, M., Killian, J. K., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci71180 · Cited by 428 · see citing works
Oldham, W. M., Clish, C. B., Yang, Y., & Loscalzo, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.021 · Cited by 364 · cited 8× · see citing works
“In order to separate alpha-hydroxyacid enantiomers, we adapted a liquid chromatography-mass spectrometry (LC-MS) protocol involving derivatization of metabolites with the chiral compound diacetyl-L-tartaric anhydride (Supplementary Results, Supplementary Fig.”
InfluentialMullen, A. R., Hu, Z., Shi, X., Jiang, L., Boroughs, L. K., Kovacs, Z., Boriack, R., Rakheja, D., Sullivan, L. B., Linehan, W. M., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.037 · Cited by 337 · see citing works
<scp>l</scp> -2-Hydroxyglutarate: An Epigenetic Modifier and Putative Oncometabolite in Renal Cancer
Shim, E.-H., Livi, C. B., Rakheja, D., Tan, J., Benson, D., Parekh, V., Kho, E.-Y., Ghosh, A. P., Kirkman, R., Velu, S., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0696 · Cited by 280 · see citing works
A Specific, Highly Active Malate Dehydrogenase by Redesign of a Lactate Dehydrogenase Framework
Wilks, H. M., Hart, K. W., Feeney, R., Dunn, C. R., Muirhead, H., Chia, W. N., Barstow, D. A., Atkinson, T., Clarke, A. R., & Holbrook, J. J. (1988) · Science · doi:10.1126/science.3201242 · Cited by 276 · see citing works
Metabolite damage and its repair or pre-emption
Linster, C. L., SCHAFTINGEN, E. V., & Hanson, A. D. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1141 · Cited by 269 · see citing works
HIF activation by pH-dependent nucleolar sequestration of VHL
Mekhail, K., Gunaratnam, L., Bonicalzi, M.-E., & Lee, S. (2004) · Nature Cell Biology · doi:10.1038/ncb1144 · Cited by 260 · see citing works
Meister, A. (1950) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)51130-9 · Cited by 260 · see citing works
Novoa, W. B., Winer, A. D., Glaid, A. J., & Schwert, G. W. (1959) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98146-9 · Cited by 257 · see citing works
MCCE2: Improving protein pKa calculations with extensive side chain rotamer sampling
Song, Y., Mao, J., & Gunner, M. R. (2009) · Journal of Computational Chemistry · doi:10.1002/jcc.21222 · Cited by 241 · see citing works
Self-citationHuman Phosphoglycerate Dehydrogenase Produces the Oncometabolite d -2-Hydroxyglutarate
Fan, J., Teng, X., Liu, L., Mattaini, K. R., Looper, R., Heiden, M. G. V., & Rabinowitz, J. D. (2014) · ACS Chemical Biology · doi:10.1021/cb500683c · Cited by 201 · see citing works
Proto-Oncogenic Role of Mutant IDH2 in Leukemia Initiation and Maintenance
Kats, L. M., Reschke, M., Taulli, R., Pozdnyakova, O., Burgess, K., Bhargava, P., Straley, K. S., Karnik, R., Meissner, A., Small, D., et al. (2014) · Cell stem cell · doi:10.1016/j.stem.2013.12.016 · Cited by 187 · see citing works
Chen, C., Liu, Y., Lü, C., Cross, J. R., Morris, J. P., Shroff, A., Ward, P. S., Bradner, J. E., Thompson, C. B., & Lowe, S. W. (2013) · Genes & Development · doi:10.1101/gad.226613.113 · Cited by 182 · see citing works
Self-citationLeonardi, R., Subramanian, C., Jackowski, S., & Rock, C. O. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.c112.353946 · Cited by 165 · see citing works
Changes in extracellular and intracellular pH in ischemic rabbit papillary muscle.
Yan, G., & Kléber, A. G. (1992) · Circulation Research · doi:10.1161/01.res.71.2.460 · Cited by 149 · see citing works
l ‐2‐Hydroxyglutaric aciduria, a defect of metabolite repair
Rzem, R., Vincent, M., SCHAFTINGEN, E. V., & Veiga‐da‐Cunha, M. (2007) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-007-0487-0 · Cited by 149 · see citing works
Struys, E. A., Jansen, E. E. W., Verhoeven‐Duif, N. M., & Jakobs, C. (2004) · Clinical Chemistry · doi:10.1373/clinchem.2004.033399 · Cited by 147 · see citing works
Design and synthesis of new enzymes based on the lactate dehydrogenase framework
Dunn, C. R., Wilks, H. M., Halsall, D. J., Atkinson, T., Clarke, A. R., Muirhead, H., & Holbrook, J. J. (1991) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.1991.0047 · Cited by 128 · see citing works
A Tale of Two Subunits: How the Neomorphic R132H IDH1 Mutation Enhances Production of αHG
Pietrak, B., Zhao, H., Qi, H., Quinn, C. J., Gao, E. N., Boyer, J. G., Concha, N. O., Brown, K., Duraiswami, C., Wooster, R. F., et al. (2011) · Biochemistry · doi:10.1021/bi200499m · Cited by 109 · see citing works
Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases
Tarhonskaya, H., Rydzik, A. M., Leung, I. K. H., Loik, N. D., Chan, M. C., Kawamura, A., McCullagh, J. S. O., Claridge, T. D. W., Flashman, E., & Schofield, C. J. (2014) · Nature Communications · doi:10.1038/ncomms4423 · Cited by 80 · see citing works
Mutant IDH1 Enhances the Production of 2-Hydroxyglutarate Due to Its Kinetic Mechanism
Rendina, A. R., Pietrak, B., Smallwood, A. M., Zhao, H., Qi, H., Quinn, C. J., Adams, N. D., Concha, N. O., Duraiswami, C., Thrall, S. H., et al. (2013) · Biochemistry · doi:10.1021/bi400514k · Cited by 79 · see citing works
α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism
Tokonami, N., Morla, L., Centeno, G., Mordasini, D., Ramakrishnan, S. K., Nikolaeva, S. D., Wagner, C. A., Bonny, O., Houillier, P., Doucet, A., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67562 · Cited by 78 · see citing works
A sensitive fluorimetric assay for pyruvate
Zhu, A., Romero, R. J., & Petty, H. R. (2009) · Analytical Biochemistry · doi:10.1016/j.ab.2009.09.017 · Cited by 77 · see citing works
Reduction of α-Ketoglutarate by Homogeneous Lactic Dehydrogenase X of Testicular Tissue
Schatz, L., & Segal, H. L. (1969) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)94331-0 · Cited by 72 · see citing works
Structures of lactate dehydrogenase A (LDHA) in apo, ternary and inhibitor-bound forms
Kolappan, S., Shen, D. L., Mosi, R., Sun, J., McEachern, E. J., Vocadlo, D. J., & Craig, L. (2015) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s1399004714024791 · Cited by 70 · see citing works
Haliloğlu, G., Jobard, F., Oguz, K., Anlar, B., Akalan, N., Coşkun, T., Sass, J. O., Fischer, J., & Topcu, M. (2008) · Neuropediatrics · doi:10.1055/s-2008-1081217 · Cited by 69 · see citing works
A Mouse Model of L-2-Hydroxyglutaric Aciduria, a Disorder of Metabolite Repair
Rim, R., Achouri, Y., Marbaix, É., Schakman, O., Wiame, E., Marie, S., Gailly, P. L., Vincent, M., Veiga‐da‐Cunha, M., & SCHAFTINGEN, E. V. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119540 · Cited by 58 · see citing works
Brain Levels of NADH and NAD+ Under Hypoxic and Hypoglycaemic Conditions In Vitro
Garofalo, O., COX, D. W. G., & Bachelard, H. S. (1988) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1988.tb04851.x · Cited by 57 · see citing works
Mattaini, K. R., Brignole, E. J., Kini, M., Davidson, S. M., Fiske, B. P., Drennan, C. L., & Vander Heiden, M. G. (2015) · Cancer & Metabolism · doi:10.1186/s40170-015-0131-7 · Cited by 38 · see citing works
pH Dependence of Lactate Dehydrogenase Isozyme Inhibition by Substrate
Vesell, E. S. (1966) · Nature · doi:10.1038/210421a0 · Cited by 33 · see citing works
Intracellular pH changes induced by hypoxia and anoxia in isolated sheep heart Purkinje fibres
Bright, C. M., & Ellis, D. (1992) · Experimental Physiology · doi:10.1113/expphysiol.1992.sp003570 · Cited by 31 · see citing works
Villoutreix, B. O., Dahlb�ck, B., Borgel, D., Gandrille, S., & Muller, Y. A. (2001) · Proteins Structure Function and Bioinformatics · doi:10.1002/1097-0134(20010501)43:2 · Cited by 26 · see citing works
DESIGN AND SYNTHESIS OF NEW ENZYMES BASED ON THE LACTATE DEHYDROGENASE FRAMEWORK
Cr, D., Holbrook, J. J., & Muirhead, H. (1991) · Worldwide Protein Data Bank · doi:10.2210/pdb9ldb/pdb · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial TCA cycle metabolites control physiology and disease
Martínez-Reyes, I., & Chandel, N. S. (2020) · Nature Communications · doi:10.1038/s41467-019-13668-3 · Cited by 2,813 · see citing works
Cellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond
Lee, P., Chandel, N. S., & Simon, M. C. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0227-y · Cited by 1,272 · see citing works
The Acidic Tumor Microenvironment as a Driver of Cancer
Boedtkjer, E., & Pedersen, S. F. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034627 · Cited by 1,248 · see citing works
Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021 · see citing works
Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches
de la Cruz-López, K. G., Castro-Muñoz, L. J., Reyes-Hernández, D. O., García-Carrancá, A., & Manzo-Merino, J. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01143 · Cited by 940 · see citing works
Regulation of Immunity and Inflammation by Hypoxia in Immunological Niches
Taylor, C. T., & Colgan, S. P. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.103 · Cited by 713 · see citing works
Mitochondrial signal transduction
Picard, M. A., & Shirihai, O. S. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.10.008 · Cited by 666 · see citing works
Regulation and function of the mammalian tricarboxylic acid cycle
Arnold, P. K., & Finley, L. W. S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102838 · Cited by 535 · see citing works
“This promiscuous enzymatic activity is amplified during hypoxia (175, 176) and under acidic pH (177, 178), raising the possibility that 2HG accumulation may play a regulatory role under normal physiological conditions.”
BackgroundMitochondria as Signaling Organelles Control Mammalian Stem Cell Fate
Chakrabarty, R. P., & Chandel, N. S. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.02.011 · Cited by 490 · see citing works
Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate
Chakraborty, A. A., Laukka, T., Myllykoski, M., Ringel, A. E., Booker, M. A., Tolstorukov, M. Y., Meng, Y. J., Meier, S. R., Jennings, R. B., Creech, A. L., et al. (2019) · Science · doi:10.1126/science.aaw1026 · Cited by 432 · see citing works
Systems analysis of intracellular pH vulnerabilities for cancer therapy
Persi, E., Duran‐Frigola, M., Damaghi, M., Roush, W. R., Aloy, P., Cleveland, J. L., Gillies, R. J., & Ruppin, E. (2018) · Nature Communications · doi:10.1038/s41467-018-05261-x · Cited by 410 · see citing works
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398 · see citing works
The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8
Zhang, J.-Y., Zhou, B., Sun, R.-Y., Ai, Y.-L., Cheng, K., Li, F.-N., Wang, B.-R., Liu, F.-J., Jiang, Z., Wang, W., et al. (2021) · Cell Research · doi:10.1038/s41422-021-00506-9 · Cited by 392 · see citing works
Self-citationFinley, L. W. S. (2023) · Cell · doi:10.1016/j.cell.2023.01.038 · Cited by 331 · see citing works
Oncometabolite d -2HG alters T cell metabolism to impair CD8 + T cell function
Notarangelo, G., Spinelli, J. B., Perez, E. M., Baker, G. J., Kurmi, K., Elia, I., Stopka, S. A., Baquer, G., Lin, J., Golby, A. J., et al. (2022) · Science · doi:10.1126/science.abj5104 · Cited by 292 · see citing works
The EGLN-HIF O 2 -Sensing System: Multiple Inputs and Feedbacks
Ivan, M., & Kaelin, W. G. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.06.002 · Cited by 273 · see citing works
The functional roles of TCA cycle metabolites in cancer
Eniafe, J., & Jiang, S. (2021) · Oncogene · doi:10.1038/s41388-020-01639-8 · Cited by 274 · see citing works
Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates
Ye, D., Guan, K.-L., & Xiong, Y. (2018) · Trends in Cancer · doi:10.1016/j.trecan.2017.12.005 · Cited by 242 · see citing works
Metabolic regulation of chromatin modifications and gene expression
Schvartzman, J. M., Thompson, C. B., & Finley, L. W. S. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201803061 · Cited by 233 · see citing works
Self-citation2-Oxoglutarate-dependent dioxygenases in cancer
Losman, J.-A., Koivunen, P., & Kaelin, W. G. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-00303-3 · Cited by 225 · see citing works
Chang, S., Yim, S., & Park, H. (2019) · Experimental & Molecular Medicine · doi:10.1038/s12276-019-0230-6 · Cited by 228 · see citing works
Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization
Labuschagne, C. F., Cheung, E. C., Blagih, J., Domart, M., & Vousden, K. H. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.07.014 · Cited by 223 · see citing works
Glioma stem cells and their roles within the hypoxic tumor microenvironment
Boyd, N., Tran, A. N., Bernstock, J. D., Etminan, T., Jones, A. B., Gillespie, G. Y., Friedman, G. K., & Hjelmeland, A. B. (2020) · Theranostics · doi:10.7150/thno.41692 · Cited by 218 · see citing works
AMPK–mTOR Signaling and Cellular Adaptations in Hypoxia
Chun, Y., & Kim, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22189765 · Cited by 209 · see citing works
Oxygen availability and metabolic reprogramming in cancer
Xie, H. J., & Simon, M. C. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.799973 · Cited by 203 · see citing works
Ge, T., Gu, X., Jia, R., Ge, S., Chai, P., Zhuang, A., & Fan, X. (2022) · 癌症:英文版 · doi:10.1002/cac2.12374 · Cited by 206 · see citing works
Goetzman, E. S., & Prochownik, E. V. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00129 · Cited by 199 · see citing works
Metabolic Signaling to the Nucleus in Cancer
Campbell, S. L., & Wellen, K. E. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.07.015 · Cited by 182 · see citing works
Germinal center‐derived lymphomas: The darkest side of humoral immunity
Mlynarczyk, C., Fontán, L., & Melnick, A. (2019) · Immunological Reviews · doi:10.1111/imr.12755 · Cited by 179 · see citing works
A landscape of metabolic variation across tumor types
Reznik, E., Luna, A., Aksoy, B. A., Liu, E. M., La, K., Ostrovnaya, I., Creighton, C. J., Hakimi, A. A., & Sander, C. (2018) · Cell Systems · doi:10.1016/j.cels.2017.12.014 · Cited by 172 · see citing works
Liu, Y., Guo, J., Liu, Y., Wang, K., Ding, W., Wang, H., Liu, X., Zhou, S., Lu, X., Yang, H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06841-7 · Cited by 171 · see citing works
Venneti, S., Kawakibi, A. R., Ji, S., Waszak, S. M., Sweha, S. R., Mota, M., Pun, M. J., Deogharkar, A., Chung, C., Tarapore, R. S., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0131 · Cited by 167 · see citing works
Metabolic coordination of cell fate by α-ketoglutarate-dependent dioxygenases
Baksh, S. C., & Finley, L. W. S. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.09.010 · Cited by 165 · see citing works
Metabolic remodelling during early mouse embryo development
Zhao, J., Yao, K., Yu, H., Zhang, L., Xu, Y., Chen, L., Sun, Z., Zhu, Y., Zhang, C., Qian, Y., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00464-x · Cited by 164 · see citing works
The Roles of 2-Hydroxyglutarate
Du, X., & Hu, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.651317 · Cited by 152 · see citing works
The crosstalk between HIFs and mitochondrial dysfunctions in cancer development
Bao, X., Zhang, J., Huang, G., Yan, J., Xu, C., Dou, Z., Sun, C., & Zhang, H. (2021) · Cell Death & Disease · doi:10.1038/s41419-021-03505-1 · Cited by 152 · see citing works
Mitochondrial Metabolism Regulation of T Cell–Mediated Immunity
Steinert, E. M., Vasan, K., & Chandel, N. S. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101819-082015 · Cited by 154 · see citing works
Oncogenic Activities of IDH1/2 Mutations: From Epigenetics to Cellular Signaling
Gagné, L. M., Boulay, K., Topisirović, I., Huot, M., & Mallette, F. A. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.06.002 · Cited by 141 · see citing works
Control of endothelial quiescence by FOXO-regulated metabolites
Andrade, J., Shi, C., Costa, A. S. H., Choi, J., Kim, J., Doddaballapur, A., Sugino, T., Ong, Y. T., Castro, M., Zimmermann, B., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00637-6 · Cited by 129 · see citing works
2-Hydroxyglutarate in Cancer Cells
Ježek, P. (2020) · Antioxidants & Redox Signaling · doi:10.1089/ars.2019.7902 · Cited by 130 · see citing works
Zhang, J., Yao, M., Xia, S., Zeng, F., & Liu, Q. (2025) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-024-00682-7 · Cited by 139 · see citing works
Cell fate decisions: emerging roles for metabolic signals and cell morphology
Tatapudy, S., Aloisio, F. M., Barber, D. L., & Nystul, T. G. (2017) · EMBO Reports · doi:10.15252/embr.201744816 · Cited by 123 · see citing works
Cancer Metabolism Drives a Stromal Regenerative Response
Schwörer, S., Vardhana, S. A., & Thompson, C. B. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.015 · Cited by 121 · see citing works
Self-citationFunctional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans
Ni, M., Solmonson, A., Pan, C., Yang, C., Li, D., Notzon, A., Cai, L., Guevara, G., Zacharias, L. G., Faubert, B., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.005 · Cited by 121 · see citing works
Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation
Li, T., Mao, C., Wang, X., Shi, Y., & Tao, Y. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01733-5 · Cited by 125 · see citing works
Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets
Mishra, S. K., Millman, S. E., & Zhang, L. (2022) · Blood · doi:10.1182/blood.2022018092 · Cited by 118 · see citing works
Hallmarks of Pulmonary Hypertension: Mesenchymal and Inflammatory Cell Metabolic Reprogramming
D’Alessandro, A., Kasmi, K. C. E., Plecitá‐Hlavatá, L., Ježek, P., Li, M., Zhang, H., Gupte, S. A., & Stenmark, K. R. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7217 · Cited by 110 · see citing works
Metabolic recoding of epigenetics in cancer
Wang, Y., & Lei, Q. (2018) · 癌症:英文版 · doi:10.1186/s40880-018-0302-3 · Cited by 107 · see citing works
Widespread bacterial lysine degradation proceeding via glutarate and L-2-hydroxyglutarate
Knorr, S., Sinn, M., Galetskiy, D., Williams, R. M., Wang, C., Müller, N., Mayans, O. M., Schleheck, D., & Hartig, J. S. (2018) · Nature Communications · doi:10.1038/s41467-018-07563-6 · Cited by 97 · see citing works
Red Blood Cell Metabolism In Vivo and In Vitro
D’Alessandro, A., Anastasiadi, A. T., Tzounakas, V. L., Nemkov, T. G., Reisz, J. A., Kriebardis, A. G., Zimring, J. C., Spitalnik, S. L., & Busch, M. P. (2023) · Metabolites · doi:10.3390/metabo13070793 · Cited by 100 · see citing works
An LKB1–mitochondria axis controls TH17 effector function
Baixauli, F., Piletič, K., Puleston, D. J., Villa, M., Field, C. S., Flachsmann, L. J., Quintana, A., Rana, N., Edwards-Hicks, J., Matsushita, M., et al. (2022) · Nature · doi:10.1038/s41586-022-05264-1 · Cited by 100 · see citing works
Peng, M., Yang, D., Hou, Y., Liu, S., Zhao, M., Qin, Y., Chen, R., Teng, Y., & Liu, M. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1475-7 · Cited by 96 · see citing works
RetractedDefining a metabolic landscape of tumours: genome meets metabolism
Nanda, C. S., Venkateswaran, S. V., Patani, N., & Yuneva, M. O. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0663-7 · Cited by 94 · see citing works
The multifaceted contribution of α-ketoglutarate to tumor progression: An opportunity to exploit?
Abla, H., Sollazzo, M., Gasparre, G., Iommarini, L., & Porcelli, A. M. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.031 · Cited by 96 · see citing works
Gupta, V. K., Sharma, N., Durden, B. C., Garrido, V. T., Kesh, K., Edwards, D., Wang, D., Myer, C., Mateo-Victoriano, B., Kollala, S. S., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2562 · Cited by 94 · see citing works
Shelar, S. B., Shim, E., Brinkley, G. J., Kundu, A., Carobbio, F., Poston, T. L., Tan, J. C., Parekh, V., Benson, D. G., Crossman, D. K., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1727 · Cited by 89 · see citing works
Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas
Remacha, L., Pirman, D. A., Mahoney, C. E., Coloma, J., Calsina, B., Currás-Freixes, M., Letón, R., Torres‐Pérez, R., Richter, S., Pita, G., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.02.017 · Cited by 88 · see citing works
Suzuki, J., Yamada, T., Inoue, K., Nabe, S., Kuwahara, M., Takemori, N., Takemori, A., Matsuda, S., Kanoh, M., Imai, Y., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05854-6 · Cited by 87 · see citing works
Badur, M. G., Muthusamy, T., Parker, S. J., Ma, S., McBrayer, S. K., Cordes, T., Magaña, J. H., Guan, K., & Metallo, C. M. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.09.074 · Cited by 82 · see citing works
Richelle, A., Chiang, A. W. T., Kuo, C., & Lewis, N. E. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006867 · Cited by 76 · see citing works
Puchalska, P., Huang, X., Martin, S. E., Han, X., Patti, G. J., & Crawford, P. A. (2018) · iScience · doi:10.1016/j.isci.2018.10.029 · Cited by 79 · see citing works
Multiple functions of pyruvate kinase M2 in various cell types
Lee, Y.-B., Min, J. K., Kim, J., Cap, K. C., Islam, R., Hossain, A. J., Dogsom, O., Hamza, A., Mahmud, S., Choi, D. R., et al. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30536 · Cited by 78 · see citing works
Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH
Nadtochiy, S. M., Wang, Y. T., Nehrke, K. W., Munger, J., & Brookes, P. S. (2017) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2018.06.007 · Cited by 74 · see citing works
Mosaoa, R., Kasprzyk-Pawelec, A., Fernandez, H. R., & Avantaggiati, M. L. (2021) · Biomolecules · doi:10.3390/biom11020141 · Cited by 76 · see citing works
Effects of lactate on metabolism and differentiation of CD4+T cells
Zhang, Y., Xing, M.-L., Fang, H.-H., Li, W., Wu, L., & Chen, Z. (2023) · Molecular Immunology · doi:10.1016/j.molimm.2022.12.015 · Cited by 69 · see citing works
Zhang, M., Gao, C., Guo, X., Guo, S., Kang, Z., Xiao, D., Yan, J., Tao, F., Zhang, W., Dong, W., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04513-0 · Cited by 66 · see citing works
Succinate-loaded tumor cell–derived microparticles reprogram tumor-associated macrophage metabolism
Lu, S., Li, J., Li, Y., Liu, S., Liu, Y., Liang, Y., Zheng, X., Chen, Y., Deng, J., Zhang, H., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adr4458 · Cited by 66 · see citing works
Mitochondrial redox and TCA cycle metabolite signaling in the heart
Vujić, A., Koo, A., Prag, H. A., & Krieg, T. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.02.041 · Cited by 62 · see citing works
Metabolic Dysregulations and Epigenetics: A Bidirectional Interplay that Drives Tumor Progression
Crispo, F., Condelli, V., Lepore, S., Notarangelo, T., Sgambato, A., Esposito, F., Maddalena, F., & Landriscina, M. (2019) · Cells · doi:10.3390/cells8080798 · Cited by 61 · see citing works
Laukka, T., Myllykoski, M., Looper, R., & Koivunen, P. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.06.048 · Cited by 65 · see citing works
The Bidirectional Relationship Between Cancer Epigenetics and Metabolism
Izzo, L., Affronti, H. C., & Wellen, K. E. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-070820-035832 · Cited by 60 · see citing works
Cytosolic and mitochondrial NADPH fluxes are independently regulated
Niu, X., Stancliffe, E., Gelman, S. J., Wang, L., Schwaiger-Haber, M., Rowles, J. L., Shriver, L. P., & Patti, G. J. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01283-9 · Cited by 60 · see citing works
Mitochondria and Hypoxia: Metabolic Crosstalk in Cell-Fate Decisions
Bargiela, D., Burr, S. P., & Chinnery, P. F. (2018) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2018.02.002 · Cited by 60 · see citing works
Hypoxia signaling: Challenges and opportunities for cancer therapy
Ivan, M., Fishel, M. L., Tudoran, O. M., Pollok, K. E., Wu, X., & Smith, P. J. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.10.002 · Cited by 56 · see citing works
Therapeutic Targeting of Cancer Stem Cells: Integrating and Exploiting the Acidic Niche
Linden, C. V., & Corbet, C. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00159 · Cited by 58 · see citing works
Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations
Hvinden, I. C., Cadoux-Hudson, T. A. D., Schofield, C. J., & McCullagh, J. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100469 · Cited by 59 · see citing works
The metabolic axis of macrophage and immune cell polarization
Hobson-Gutierrez, S., & Carmona‐Fontaine, C. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.034462 · Cited by 55 · see citing works
Self-citationDecoding the Rosetta stone of mitonuclear communication
English, J., Son, J. M., Cardamone, M. D., Lee, C., & Perissi, V. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105161 · Cited by 55 · see citing works
KDM6 Demethylases and Their Roles in Human Cancers
Hua, C., Chen, J., Li, S., Zhou, J., Fu, J., Sun, W., & Wang, W. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.779918 · Cited by 56 · see citing works
Bailey, P. S. J., Ortmann, B. M., Martinelli, A. W., Houghton, J. W., Costa, A. S. H., Burr, S. P., Antrobus, R., Frezza, C., & Nathan, J. A. (2020) · Nature Communications · doi:10.1038/s41467-020-17862-6 · Cited by 51 · see citing works
Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma
Jiang, H., Greathouse, R. L., Tiche, S. J., Zhao, M., He, B., Li, Y., Li, A. M., Forgo, B. L., Yip, M., Li, A., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-1029 · Cited by 50 · see citing works
Majd, H., King, M. S., Smith, A. C., & Kunji, E. R. S. (2017) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2017.10.002 · Cited by 53 · see citing works
Osawa, T., Shimamura, T., Saito, K., Hasegawa, Y., Ishii, N., Nishida, M., Ando, R., Kondo, A., Anwar, M., Tsuchida, R., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.087 · Cited by 53 · see citing works
Metabolism-driven chromatin dynamics: Molecular principles and technological advances
Sahu, V., & Lü, C. (2025) · Molecular Cell · doi:10.1016/j.molcel.2024.12.012 · Cited by 54 · see citing works
New concepts in feedback regulation of glucose metabolism
Locasale, J. W. (2017) · Current Opinion in Systems Biology · doi:10.1016/j.coisb.2017.11.005 · Cited by 52 · see citing works
Synaptic activity‐induced glycolysis facilitates membrane lipid provision and neurite outgrowth
Segarra‐Mondejar, M., Casellas‐Díaz, S., Ramiro‐Pareta, M., Müller‐Sánchez, C., Riera, A. M., Hermelo, I., Reina, M., Aragonés, J., Martínez-Estrada, O. M., & Soriano, F. X. (2018) · The EMBO Journal · doi:10.15252/embj.201797368 · Cited by 52 · see citing works
Metabolite damage and repair in metabolic engineering design
Sun, J., Jeffryes, J. G., Henry, C. S., Bruner, S. D., & Hanson, A. D. (2017) · Metabolic Engineering · doi:10.1016/j.ymben.2017.10.006 · Cited by 48 · see citing works
Zhang, W., Zhang, M., Gao, C., Zhang, Y., Ge, Y., Guo, S., Guo, X., Zhou, Z., Liu, Q., Zhang, Y., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1619034114 · Cited by 46 · see citing works
Gao, Y.-M., Zimmer, J. T., Vasic, R., Liu, C., Gbyli, R., Zheng, S.-J., Patel, A., Liu, W., Qi, Z., Li, Y.-P., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113163 · Cited by 43 · see citing works
Metabolite regulation of epigenetics in cancer
Wang, P., Chen, L., Xiong, Y., & Ye, D. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114815 · Cited by 48 · see citing works
LDHA as a regulator of T cell fate and its mechanisms in disease
Dai, M., Wang, L., Yang, J., Chen, J., Dou, X., Chen, R., Ge, Y., & Lin, Y. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114164 · Cited by 45 · see citing works
Resistance of Hypoxic Cells to Ionizing Radiation Is Mediated in Part via Hypoxia-Induced Quiescence
Menegakis, A., Klompmaker, R., Vennin, C., Arbusà, A., Damen, M. P. F., van den Broek, B., Zips, D., van Rheenen, J., Krenning, L., & Medema, R. H. (2021) · Cells · doi:10.3390/cells10030610 · Cited by 44 · see citing works
Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis
Sharma, S., Agnihotri, N., & Kumar, S. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114943 · Cited by 42 · see citing works
Karigane, D., & Takubo, K. (2017) · International Journal of Hematology · doi:10.1007/s12185-017-2261-x · Cited by 40 · see citing works
Bailey, P. S. J., & Nathan, J. A. (2018) · Biomedicines · doi:10.3390/biomedicines6020060 · Cited by 41 · see citing works
Metabolic underpinnings of leukemia pathology and treatment
Nemkov, T. G., D’Alessandro, A., & Reisz, J. A. (2018) · Cancer Reports · doi:10.1002/cnr2.1139 · Cited by 41 · see citing works
Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate
Zhao, M., Yao, P., Mao, Y., Wu, J., Wang, W., Geng, C., Cheng, J., Du, W., & Jiang, P. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00532-w · Cited by 40 · see citing works
Mitochondrial Redox Metabolism: The Epicenter of Metabolism during Cancer Progression
Choudhury, F. K. (2021) · Antioxidants · doi:10.3390/antiox10111838 · Cited by 43 · see citing works
Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases
Seim, G. L., John, S. V., Arp, N. L., Fang, Z., Pagliarini, D. J., & Fan, J. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01153-w · Cited by 38 · see citing works
Malate initiates a proton-sensing pathway essential for pH regulation of inflammation
Chen, Y., Shi, R., Xiang, Y., Fan, L.-P., Tang, H., He, G., Zhou, M., Feng, X., Tan, J., Huang, P., et al. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02076-9 · Cited by 27 · see citing works
- Authors
- Intlekofer, A. M., Wang, B., Liu, H., Shah, H., Carmona-Fontaine, C., Rustenburg, A. S., Salah, S., Gunner, M. R., Chodera, J. D., Cross, J. R., & Thompson, C. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- City College of New York (US)
- Corresponding author
- Thompson, Craig B
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2017-03-06
- Volume
- 13
- Issue
- 5
- Pages
- 494-500
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5516644
- OpenAlex
- W2594191418
- Cited by
- 268
- References
- 63
- Citations by year
- 2026: 21 · 2025: 29 · 2024: 28 · 2023: 25 · 2022: 28 · 2021: 40 · 2020: 27 · 2019: 28 · 2018: 26 · 2017: 14
- FWCI
- 8.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CUNY Academic Works (City University of New York) (submittedVersion)
- Funders
- National Cancer Institute (R00CA191021, K08CA201483, K99CA191021, R01CA177828, R01CA168802, P30CA008748)
- National Institute on Minority Health and Health Disparities (G12MD007603)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- L-2-hydroxyglutarate, lactate dehydrogenase, malate dehydrogenase, stereospecific reduction, alpha-ketoglutarate, low pH, protonation, substrate binding pocket, hypoxia, HIF-1α stabilization, IDH mutation, oxygen limitation, tumor microenvironment
- MeSH terms
- Glutarates, Humans, Hydrogen-Ion Concentration, Ketoglutaric Acids, L-Lactate Dehydrogenase, Malate Dehydrogenase, Gas Chromatography-Mass Spectrometry, Stereoisomerism, Molecular Structure, Biocatalysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review