Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease.

1. Sci Adv. 2019 May 22;5(5):eaaw4543. doi: 10.1126/sciadv.aaw4543. eCollection 2019 May. Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease. Tommasini-Ghelfi S(1)(2), Murnan K(1)(2), Kouri FM(1)(2), Mahajan AS(1)(2), May JL(1)(2), Stegh AH(1)(2). Author information: (1)Ken and Ruth Davee Department of Neurology, The Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 East Superior, Chicago, IL 60611, USA. (2)International Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA. Isocitrate dehydrogenases (IDHs) are critical metabolic enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG), NAD(P)H, and CO2. IDHs epigenetically control gene expression through effects on αKG-dependent dioxygenases, maintain redox balance and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis, and regulate respiration and energy production through generation of NADH. Cancer-associated mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effect. Mutant enzymes produce (R)-2-hydroxyglutarate, which in turn inhibits αKG-dependent dioxygenase function, resulting in a global hypermethylation phenotype, increased tumor cell multipotency, and malignancy. Recent studies identified wild-type IDHs as critical regulators of normal organ physiology and, when transcriptionally induced or down-regulated, as contributing to cancer and neurodegeneration, respectively. We describe how mutant and wild-type enzymes contribute on molecular levels to disease pathogenesis, and discuss efforts to pharmacologically target IDH-controlled metabolic rewiring. DOI: 10.1126/sciadv.aaw4543 PMCID: PMC6530995 PMID: 31131326 [Indexed for MEDLINE]