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Review
. 2015 Aug:152:54-62.
doi: 10.1016/j.pharmthera.2015.05.003. Epub 2015 May 5.

Metabolic consequences of oncogenic IDH mutations

Seth J Parker  1 , Christian M Metallo  2
Affiliations
Review

Metabolic consequences of oncogenic IDH mutations

Seth J Parker et al. Pharmacol Ther. 2015 Aug.

Abstract

Specific point mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in a variety of cancers, including acute myeloid leukemia (AML), low-grade gliomas, and chondrosarcomas. These mutations inactivate wild-type enzymatic activity and convey neomorphic function to produce d-2-hydroxyglutarate (d-2HG), which accumulates at millimolar levels within tumors. d-2HG can impact α-ketoglutarate-dependent dioxygenase activity and subsequently affect various cellular functions in these cancers. Inhibitors of the neomorphic activity of mutant IDH1 and IDH2 are currently in Phase I/II clinical trials for both solid and blood tumors. As IDH1 and IDH2 represent key enzymes within the tricarboxylic acid (TCA) cycle, mutations have significant impact on intermediary metabolism. The loss of some wild-type metabolic activity is an important, potentially deleterious and therapeutically exploitable consequence of oncogenic IDH mutations and requires continued investigation in the future. Here we review how IDH1 and IDH2 mutations influence cellular metabolism, epigenetics, and other biochemical functions, discussing these changes in the context of current efforts to therapeutically target cancers bearing these mutations.

Keywords: Glucose oxidation; Metabolism; Mutant IDH inhibitors; Mutant IDH1 and IDH2; NADPH; Reductive carboxylation.

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Conflict of interest statement

Conflict of Interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Multiple cellular pathways are affected by mutations in IDH1 and IDH2. Metabolites involved in these reactions are critical for glucose, glutamine, NADPH, amino acid, and lipid metabolism as well as epigenetic regulation.
Figure 2
Figure 2
Biochemical pathways involved in intermediary metabolism. Glycolysis and glucose entry into the TCA cycle is regulated by the activity of lactate dehydrogenase (LDHA and LDHB), pyruvate dehydrogenase (PDH), and pyruvate carboxylation (PC). IDH1 and IDH2 are cytosolic and mitochondrial enzymes, respectively, that are critical for the metabolism of glucose- and glutamine- derived carbons. NADPH produced by either IDH1 or IDH2 is critical for maintaining the redox state in subcellular compartments. AcCoA: acetyl-coenzyme A, aKG: alpha-ketoglutarate, Cit: citrate, D-2HG: D-2-hydroxyglutarate, Fum: fumarate, ICT: isocitrate, Lac: lactate, Mal: malate, Oac: oxaloacetate, Pyr: pyruvate, Suc: succinate.
See this image and copyright information in PMC

References

    1. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224(3):334–343. - PubMed
    1. Balendiran GK, Dabur R, Fraser D. The role of glutathione in cancer. Cell Biochem Funct. 2004;22(6):343–352. - PubMed
    1. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008;116(6):597–602. - PubMed
    1. Berwick DC, Hers I, Heesom KJ, Moule SK, Tavare JM. The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J Biol Chem. 2002;277(37):33895–33900. - PubMed
    1. Birner P, Pusch S, Christov C, Mihaylova S, Toumangelova-Uzeir K, Natchev S, et al. Mutant IDH1 inhibits PI3K/Akt signaling in human glioma. Cancer. 2014;120(16):2440–2447. - PubMed