1.1.1.42 Isocitrate dehydrogenases: Introduction

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Isocitrate dehydrogenase (IDH) enzymes catalyze the oxidative decarboxylation of isocitrate to produce α-ketoglutarate and carbon dioxide. IDH1 and IDH2 isozymes use NADP+ as a cofactor, whereas IDH3 uses NAD+ as cofactor within the citric acid cycle. IDH1 and IDH2 are homodimers and IDH3 is a heterotetramer composed of α, β and γ subunits in a 2:1:1 stoichiometry. Mutations in IDH genes are associated with certain brain tumours [1-2] and acute myeloid leukemia (AML) cells [8]. In general these mutations (for example IDH1R132H) change the function of the enzymes, reducing production of NADPH and causing production of 2-hydroxyglutarate (2-HG) [3,5], an oncometabolite [4]. Supra-normal levels of 2-HG causes hypermethylation of epigenetic targets [6], leading to malignant transformation [7]. IDH oncogenes have therefore become novel metabolism targets in brain cancers and leukemia.

References

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1. Bleeker FE, Molenaar RJ, Leenstra S. (2012) Recent advances in the molecular understanding of glioblastoma. J. Neurooncol.108 (1): 11-27. [PMID:22270850]

2. Cohen AL, Holmen SL, Colman H. (2013) IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep13 (5): 345. [PMID:23532369]

3. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC et al.. (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature462 (7274): 739-44. [PMID:19935646]

4. Garber K. (2010) Oncometabolite? IDH1 discoveries raise possibility of new metabolism targets in brain cancers and leukemia. J. Natl. Cancer Inst.102 (13): 926-8. [PMID:20576929]

5. Jin G, Reitman ZJ, Spasojevic I, Batinic-Haberle I, Yang J, Schmidt-Kittler O, Bigner DD, Yan H. (2011) 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations. PLoS ONE6 (2): e16812. [PMID:21326614]

6. Molenaar RJ, Radivoyevitch T, Maciejewski JP, van Noorden CJ, Bleeker FE. (2014) The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation. Biochim. Biophys. Acta1846 (2): 326-41. [PMID:24880135]

7. Stein EM. (2015) Molecular Pathways: IDH2 Mutations, Co-opting Cellular Metabolism for Malignant Transformation. Clin. Cancer Res.,  [Epub ahead of print]. [PMID:26553750]

8. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE et al.. (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell17 (3): 225-34. [PMID:20171147]

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1.1.1.42 Isocitrate dehydrogenases, introduction. Last modified on 15/12/2015. Accessed on 16/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=922.