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Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism
Open accessAbstract
Dysregulation of metabolism is a common phenomenon in cancer cells. The NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2-4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of D-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.
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“There is a renewed interest in the area of cancer metabolism with metabolic reprogramming coined as a hallmark of cancer based on the discovery of mutations and alterations in IDH1 and IDH2 along with succinate dehydrogenase (SDH), fumarate hydratase (FH), and pyruvate kinase M2 (PKM2) [41, 42].”
From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [42]
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“It became extremely relevant to the field of cancer metabolism when isocitrate dehydrogenase 1/2 (IDH1/2) mutations in glioma and acute myeloid leukemia were discovered (Dang et al. 2010; Reitman and Yan 2010).”
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“IDH2 is located in the mitochondria and catalyzes the isocitrate to aketoglutarate reaction in the TCA cycle.(70) The occurrence of IDH1 mutations correlated with approximately twofold diminished NADP-dependent IDH activity, and total NADPH production is hampered by 38% in GBM harboring the IDH1 mutation.”
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“The mutated forms of IDHs (58) produce 2-HG instead of α-KG essential for PHD function (59).”
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“coli BL21 DE(3) was transformed with the expression construct.”
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“Cancer-associated mutations in both IDH1 and IDH2 occur early in carcinogenesis (212) and lead to NADPHdependent generation of the novel oncometabolite 2-hydroxyglutarate (2HG) which inhibits αKG-dependent enzymes important for hypoxic gene regulation and competes with biosynthetic reactions and GSH generation for ava…”
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“Some isoforms of these enzymes (IDH 1-3) catalyze the oxidative decarboxylation of isocitrate to >-KG in the TCA cycle (67).”
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FoxO transcription factors in cancer metabolism
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“Interestingly, oncogenic mutations in IDH have been characterized in several cancer types [48, 49].”
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“IDH1 and IDH2 function at a crossroads involving cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration and oxygen-sensing signal transduction [23].”
BackgroundDemographic variation in incidence of adult glioma by subtype, United States, 1992-2007
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“Given that among malignancies (brain or otherwise), non-GBM (as well as secondary GBM) are unique in exhibiting a high frequency (as high as 80%) of IDH mutations [15,16,29,30], which appear to be early events in nonGBM development [16], one can speculate that these mutations drive an atypical path to malignancy.”
BackgroundIsocitrate dehydrogenases in physiology and cancer: biochemical and molecular insight
Al‐Khallaf, H. (2017) · Cell & Bioscience · doi:10.1186/s13578-017-0165-3 · Cited by 133
“because of its structural similarity to 2KG) [100, 101], it is possible that it also inhibits the Wt-Wt dimer form of the respective IDH isoform and that might explain the dominant negative effect of heterozygous arginine substitution (Fig.”
BackgroundDiscovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor
Cho, Y. S., Levell, J. R., Liu, G., Caferro, T. R., Sutton, J. C., Shafer, C. M., Costales, A., Manning, J. R., Zhao, Q. L., Sendzik, M., et al. (2017) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.7b00342 · Cited by 125
Fathi, A. T., Sadrzadeh, H., Borger, D. R., Ballen, K. K., Amrein, P. C., Attar, E. C., Foster, J., Burke, M. E., Lopez, H. U., Matulis, C. R., et al. (2012) · Blood · doi:10.1182/blood-2012-06-438267 · Cited by 125
Zou, P., Xu, H., Chen, P., Yan, Q., Zhao, L., Zhao, P., & Gu, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068782 · Cited by 127
Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side
Prieto-Bermejo, R., Romo-González, M., Pérez‐Fernández, A., Ijurko, C., & Hernández‐Hernández, Á. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0797-0 · Cited by 126
“Instead of oxidising isocitrate to α-ketoglutarate (α-KG), rendering NADPH, the mutant enzymes reduce α-KG to 2-hydroxyglutarate (2-HG) with the consumption of NADPH [133].”
BackgroundChen, X., Yu, J., Tian, H., Shan, Z., Liu, W., Pan, Z., & Ren, J. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28692 · Cited by 118
“Some glycolytic genes are overexpressed in a variety of tumors, and are associated with malignancy and invasiveness, like hexokinase 2 (HK2), pyruvate kinase isozyme M2, lactate dehydrogenase A (LDHA), as well as glucose transporter (GLUT; Reitman & Yan, 2010; Teoh & Lunt, 2018).”
BackgroundGenetic alterations in Krebs cycle and its impact on cancer pathogenesis
Sajnani, K., Islam, F., Smith, R. A., Gopalan, V., & Lam, A. K.-Y. (2017) · Biochimie · doi:10.1016/j.biochi.2017.02.008 · Cited by 121
Wang, Y., Zhang, X., Wang, Z., Hu, Q., Wu, J., Li, Y., Ren, X., Wu, T., Tao, X., Chen, X., et al. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.07.016 · Cited by 117
Ho, P. A., Kutny, M. A., Alonzo, T. A., Gerbing, R. B., Joaquin, J., Raimondi, S. C., Gamis, A. S., & Meshinchi, S. (2011) · Pediatric Blood & Cancer · doi:10.1002/pbc.23179 · Cited by 123
“mutations have been reported in both adult AML and adult gliomas, while R140 mutations are exclusive to AML [14].”
Jin, G., Reitman, Z. J., Spasojevic, I., Batinic-Haberle, I., Yang, J., Schmidt-Kittler, O., Bigner, D. D., & Yan, H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016812 · Cited by 112
“in either gene are mutually exclusive in cancer (for reviews, see [10,11]).”
BackgroundInfluentialSelf-citationTargeting Cancer Metabolism - Revisiting the Warburg Effects
Tran, Q., Lee, H., Park, J., Kim, S., & Park, J. (2016) · Toxicological Research · doi:10.5487/tr.2016.32.3.177 · Cited by 116
The Multifaceted Regulation of Mitochondria in Ferroptosis
Wu, H., Wang, F., Ta, N., Zhang, T., & Gao, W. (2021) · Life · doi:10.3390/life11030222 · Cited by 111
“By using a compound screening with high cell-line-selective lethality, NADPH was identified as a biomarker for ferroptotic sensitivity across multiple cell lines [188].”
BackgroundInfluentialWu, H., Ying, M., & Hu, X. (2016) · Oncotarget · doi:10.18632/oncotarget.9746 · Cited by 114
“Some cancer cells also exhibited Impaired mitochondria metabolism, including mutations of succinate dehydrogenase [14], fumerate hydratase [15], isocitrate dehydrogenase 2 [16-18] in Krebs cycle, and mutations in mictochondria DNA that affects respiratory chain, among others.”
BackgroundKaminska, B., Czapski, B., Guzik, R., Król, S. K., & Gielniewski, B. (2019) · Molecules · doi:10.3390/molecules24050968 · Cited by 113
“IDH1 mainly occurs in the cytoplasm and peroxisomes, while IDH2 and IDH3 are found in the mitochondrial matrix [5].”
BackgroundLee, S., Jin, U.-H., Kang, J. H., Kim, S. B., Guthrie, A. S., Sreevalsan, S., Lee, J., & Safe, S. H. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0567 · Cited by 109
“IDH1 plays a critical role in the citric acid cycle and the generation of reducing equivalents, and the relative expression of wild-type andmutant IDH1 have both functional and prognostic significance in cancer (36, 37).”
BackgroundIsocitrate dehydrogenase inhibitors in acute myeloid leukemia
Liu, X., & Gong, Y. (2019) · Biomarker Research · doi:10.1186/s40364-019-0173-z · Cited by 111
“IDH1 and IDH2 are located in the cytoplasm and mitochondria, respectively, while IDH3 is located in the mitochondrial matrix [13].”
BackgroundMolecular pathology in adult high‐grade gliomas: from molecular diagnostics to target therapies
Masui, K., Cloughesy, T. F., & Mischel, P. S. (2011) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2011.01238.x · Cited by 113
“chromosome 15q26 produces an enzyme that plays the same role in mitochondria [43].”
BackgroundThe Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells
Smolková, K., & Ježek, P. (2012) · International Journal of Cell Biology · doi:10.1155/2012/273947 · Cited by 114
“IDH3 encodes a mitochondrial matrix NAD+-dependent octameric IDH3 (4α2β2γ subunits [25]) that acts in the Krebs cycle.”
BackgroundInfluentialReductive carboxylation epigenetically instructs T cell differentiation
Jaccard, A., Wyss, T., Maldonado‐Pérez, N., Rath, J. A., Bevilacqua, A., Peng, J.-J., Lepez, A., Gunten, C. V., Franco, F., Kao, K., et al. (2023) · Nature · doi:10.1038/s41586-023-06546-y · Cited by 105
Mutational landscape of AML with normal cytogenetics: Biological and clinical implications
Martelli, M. P., Sportoletti, P., Tiacci, E., Martelli, M. F., & Falini, B. (2012) · Blood Reviews · doi:10.1016/j.blre.2012.11.001 · Cited by 104
When the good go bad: Mutant NPM1 in acute myeloid leukemia
Kunchala, P., Kuravi, S., Jensen, R. A., McGuirk, J. P., & Balusu, R. (2017) · Blood Reviews · doi:10.1016/j.blre.2017.11.001 · Cited by 103
Hu, X., Chao, M., & Wu, H. (2017) · Signal Transduction and Targeted Therapy · doi:10.1038/sigtrans.2016.47 · Cited by 102
Gelman, S. J., Naser, F. J., Mahieu, N. G., McKenzie, L. D., Dunn, G. P., Chheda, M. G., & Patti, G. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.050 · Cited by 95
“Our data suggest that 2-HG synthesis is regulated by NADPH availability, which is consistent with what is known about the regulation of the wild-type IDH enzyme (Leonardi et al., 2012; Reitman and Yan, 2010).”
Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH Mutations in Glioblastoma
Krell, D., Assoku, M., Galloway, M., Mulholland, P. J., Tomlinson, I. P. M., & Bardella, C. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019868 · Cited by 94
“IDH1 is localised to the cytoplasm and peroxisomes, it is highly expressed in the liver and to a lesser level in other tissues [4].”
Fathi, A. T., & Abdel-Wahab, O. I. (2011) · Advances in Hematology · doi:10.1155/2012/469592 · Cited by 95
“Some investigators have suggested that accumulation of 2-HG plays an important role in this process, the “gain of function” neomorphic enzyme activity that promotes cancer [9, 18, 19].”
BackgroundWrzeszczyński, K. O., Varadan, V., Byrnes, J., Lum, E., Kamalakaran, S., Levine, D. A., Dimitrova, N., Zhang, M. Q., & Lucito, R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028503 · Cited by 89
“IDH1 has been implicated as a prognosis positive biomarker in glioblastoma and AML IDH1/2 mutants show hypermethylation in comparison to other AML subtypes [53,54].”
BackgroundWild-type isocitrate dehydrogenase under the spotlight in glioblastoma
Alzial, G., Renoult, O., Paris, F., Gratas, C., Clavreul, A., & Pecqueur, C. (2021) · Oncogene · doi:10.1038/s41388-021-02056-1 · Cited by 101
“These 3 IDH isoforms have overlapping but nonredundant roles in metabolism including, but not limited to, mitochondrial oxidative phosphorylation, glutamine metabolism, lipogenesis, glucose sensing, and regulation of cellular redox status [12, 13] (Fig.”
BackgroundReitman, Z. J., Duncan, C. G., Poteet, E. C., Winters, A., Yan, L., Gooden, D. M., Spasojević, I., Boros, L. G., Yang, S.-H., & Yan, H. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.575183 · Cited by 93
Self-citationDrabovich, A. P., Pavlou, M. P., Dimitromanolakis, A., & Diamandis, E. P. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.015214 · Cited by 90
“Here, we searched our MCF-7 MS/MS identification data and found no known IDH2 mutations (R172K, R172M, R172W) (50).”
MethodThe Role of Inflammation in Brain Cancer
Sowers, J. L., Johnson, K. M., Conrad, C. C., Patterson, J. T., & Sowers, L. C. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-3-0348-0837-8_4 · Cited by 93
Chemical, Target, and Bioactive Properties of Allosteric Modulation
van Westen, G. J. P., Gaulton, A., & Overington, J. P. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003559 · Cited by 90
“Isocitrate dehydrogenase 1 and 2 (ICDH)) [75], and class C GPCRs [26].”
BackgroundNon-glucose metabolism in cancer cells—is it all in the fat?
Biswas, S., Lunec, J., & Bartlett, K. (2012) · Cancer and Metastasis Reviews · doi:10.1007/s10555-012-9384-6 · Cited by 86
“However, mutated IDH1 could also be hypothesized to have suppressive effects on tumor growth by reducing NADPH levels [39, 41], thus attenuating NADPH-dependent FASN activity, which would in turn attenuate LCFA synthesis and subsequently reduce FA metabolism-dependent tumor growth, which would precipitate tumor stasis…”
BackgroundA Metabolism Toolbox for CAR T Therapy
Xu, X., Gnanaprakasam, J. R., Sherman, J. W., & Wang, R. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00322 · Cited by 82
Molecular Diagnostics of Gliomas
Nikiforova, M. N., & Hamilton, R. L. (2011) · Archives of Pathology & Laboratory Medicine · doi:10.5858/2010-0649-rair.1 · Cited by 83
BRCA1 Induces Major Energetic Metabolism Reprogramming in Breast Cancer Cells
Privat, M., Radosevic‐Robin, N., Aubel, C., Cayre, A., Penault-Llorca, F. M., Marceau, G., Sapin, V., Bignon, Y., & Morvan, D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102438 · Cited by 82
“IDH2 is a reverse enzyme which role could be to convert oxoglutarate to isocitrate [28].”
BackgroundBorkum, J. M. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03335-9 · Cited by 83
“Moreover, because NADPH does not pass from the cytosol to the inner mitochondrial membrane [100], there are separate pathways for these two cellular compartments.”
Backgroundde la Fuente, M. I., Colman, H., Rosenthal, M. A., Tine, B. A. V., Levacic, D., Walbert, T., Gan, H. K., Vieito, M., Milhem, M. M., Lipford, K., et al. (2022) · Neuro-Oncology · doi:10.1093/neuonc/noac139 · Cited by 82
“Median (IQR) years since initial diagnosis 6 (4-11)”
BackgroundTargeting the NRF2/KEAP1 pathway in cervical and endometrial cancers
Tossetta, G., & Marzioni, D. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.175503 · Cited by 81
A Review of Radiomics and Deep Predictive Modeling in Glioma Characterization
Gore, S. A., Chougule, T., Jagtap, J., Saini, J. S., & Ingalhalikar, M. (2020) · Academic Radiology · doi:10.1016/j.acra.2020.06.016 · Cited by 80
Fathi, A. T., Sadrzadeh, H., Comander, A. H., Higgins, M. J., Bardia, A., Perry, A. M., Burke, M. E., Silver, R. M., Matulis, C. R., Straley, K. S., et al. (2014) · The Oncologist · doi:10.1634/theoncologist.2013-0417 · Cited by 77
Okita, Y., Narita, Y., Miyakita, Y., Ohno, M., Matsushita, Y., Fukushima, S., Sumi, M., Ichimura, K., Kayama, T., & Shibui, S. (2012) · International Journal of Oncology · doi:10.3892/ijo.2012.1564 · Cited by 75
Isocitrate dehydrogenase mutations in leukemia
McKenney, A. S., & Levine, R. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67266 · Cited by 78
“…as the allosterically regulated, rate-limiting enzymatic step in the TCA cycle, while the other two isoforms, which are mutated in cancer, utilize this catalytic process in additional contexts including metabolism and glucose sensing (IDH1) and regulation of oxidative respiration (IDH2) (11, 12).”
Metadata
- Authors
- Reitman, Z. J., & Yan, H.
- Affiliations
- Duke University (US)
- Venue
- JNCI Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-05-31
- Volume
- 102
- Issue
- 13
- Pages
- 932-941
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- PMC
- PMC2897878
- OpenAlex
- W2124951199
- Cited by
- 562
- References
- 88
- Citations by year
- 2026: 22 · 2025: 41 · 2024: 20 · 2023: 33 · 2022: 31 · 2021: 44 · 2020: 40 · 2019: 43 · 2018: 40 · 2017: 36 · 2016: 31 · 2015: 34 · 2014: 28 · 2013: 34 · 2012: 38
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Cancer Institute (R01CA118822, R01CA140316)
- National Institute of General Medical Sciences (T32GM007171)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- IDH1, IDH2, IDH1 mutation, IDH2 mutation, cancer metabolism, glioma, acute myeloid leukemia, D-2-hydroxyglutarate, oxidative stress, lipogenesis, oxygen sensing, anticancer agents
- MeSH terms
- Animals, Hypoxia, Arginine, Brain Neoplasms, Codon, Glioblastoma, Glucose, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, NADP, Neoplasms, Oligodendroglioma, Oncogenes, Signal Transduction, Up-Regulation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor
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