title: Metabolic consequences of oncogenic IDH mutations.
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.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, United States.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Parker
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, United States; Moores Cancer Center, University of California, San Diego, La Jolla, California, United States. Electronic address: cmetallo@ucsd.edu.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D002986:Clinical Trials as Topic / Q000379:methods; D004734:Energy Metabolism / Q000502:physiology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology*
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: Glucose oxidation; Metabolism; Mutant IDH inhibitors; Mutant IDH1 and IDH2; NADPH; Reductive carboxylation