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 ?-ketoglutarate (?KG) and the NADPH/CO(2)-dependent reductive carboxylation of ?KG 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 ?KG. These mutants were also defective in ICT decarboxylation and converted ?KG 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.

SUBMITTER: Leonardi R 

PROVIDER: S-EPMC3340216 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature