What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer
Open Access
- 15 April 2013
- journal article
- review article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 27 (8), 836-852
- https://doi.org/10.1101/gad.217406.113
Abstract
Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similar metabolite (R)-2-hydroxyglutarate [(R)-2HG]. Here we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.Keywords
This publication has 146 references indexed in Scilit:
- Progress in understanding 2‐hydroxyglutaric aciduriasJournal of Inherited Metabolic Disease, 2012
- Hypoxia-Inducible Factors in Physiology and MedicineCell, 2012
- Metabolic Flux and the Regulation of Mammalian Cell GrowthCell Metabolism, 2011
- Tet2 Loss Leads to Increased Hematopoietic Stem Cell Self-Renewal and Myeloid TransformationCancer Cell, 2011
- Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent DioxygenasesCancer Cell, 2011
- Hematopoietic stem cell: self‐renewal versus differentiationWires Systems Biology and Medicine, 2010
- The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-HydroxyglutarateCancer Cell, 2010
- The prognostic IDH1 R132 mutation is associated with reduced NADP+-dependent IDH activity in glioblastomaActa Neuropathologica, 2010
- An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype studyHuman Mutation, 2010
- l‐2‐Hydroxyglutaric aciduria, a defect of metabolite repairJournal of Inherited Metabolic Disease, 2007