Cited by 567Cancer, Hypoxia, and MetabolismGlioma Diagnosis and TreatmentBiochemical Acid Research Studies

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Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism

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Reitman, Z. J., Yan, H.·2010·JNCI Journal of the National Cancer Institute

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Abstract

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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“Although these mutations may prove to have been clonally selected for their ability to alter energy metabolism, there is confounding data associating their activity with elevated oxidation and stability of the HIF-1 transcription factors (Reitman and Yan, 2010), which could in turn affect genome stability and angiogen…”
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“Heterozygous mutations in either of the two isoforms of the Krebscycle enzyme isocitrate dehydrogenase (IDH1/2) occur with a high prevalence in glioma, malignant glioblastoma and acute myeloid leukaemia (Dang et al, 2010; Reitman & Yan, 2010).”
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Authors: Reitman, Z. J., & Yan, H.
Affiliations: Duke University (US)
ORCID: Reitman, Z. J.
Yan, H.
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
DOI: 10.1093/jnci/djq187
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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Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism

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