title: Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.
abstract: Point mutations of the NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.
authors.affiliation: The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Reitman
authors.forename: Genglin
authors.initials: G
authors.lastname: Jin
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Yiping
authors.initials: Y
authors.lastname: He
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
mesh_terms: D045744:Cell Line, Tumor; D004151:Dipeptides / Q000032:analysis; D005910:Glioma / Q000473:pathology; D005977:Glutarates / Q000494:pharmacology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D055442:Metabolome / Q000235:genetics*; D009154:Mutation; D009837:Oligodendroglioma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D004151:Dipeptides; D005977:Glutarates; C027172:isospaglumic acid; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase