title: Cancer-associated isocitrate dehydrogenase mutations inactivate NADPH-dependent reductive carboxylation.
abstract: Isocitrate dehydrogenase (IDH) is a reversible enzyme that catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (ICT) to α-ketoglutarate (αKG) and the NADPH/CO(2)-dependent reductive carboxylation of αKG to ICT. Reductive carboxylation by IDH1 was potently inhibited by NADP(+) and, to a lesser extent, by ICT. IDH1 and IDH2 with cancer-associated mutations at the active site arginines were unable to carry out the reductive carboxylation of αKG. These mutants were also defective in ICT decarboxylation and converted αKG to 2-hydroxyglutarate using NADPH. These mutant proteins were thus defective in both of the normal reactions of IDH. Biochemical analysis of heterodimers between wild-type and mutant IDH1 subunits showed that the mutant subunit did not inactivate reductive carboxylation by the wild-type subunit. Cells expressing the mutant IDH are thus deficient in their capacity for reductive carboxylation and may be compromised in their ability to produce acetyl-CoA under hypoxia or when mitochondrial function is otherwise impaired.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Leonardi
authors.forename: Chitra
authors.initials: C
authors.lastname: Subramanian
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
mesh_terms: D000105:Acetyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009249:NADP / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D010084:Oxidation-Reduction
chemical_list: D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D009249:NADP; D000105:Acetyl Coenzyme A; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human