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Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.

Publication ,  Journal Article
Reitman, ZJ; Jin, G; Karoly, ED; Spasojevic, I; Yang, J; Kinzler, KW; He, Y; Bigner, DD; Vogelstein, B; Yan, H
Published in: Proc Natl Acad Sci U S A
February 22, 2011

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 22, 2011

Volume

108

Issue

8

Start / End Page

3270 / 3275

Location

United States

Related Subject Headings

  • Oligodendroglioma
  • Mutation
  • Metabolome
  • Isocitrate Dehydrogenase
  • Humans
  • Glutarates
  • Glioma
  • Dipeptides
  • Cell Line, Tumor
 

Citation

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Reitman, Z. J., Jin, G., Karoly, E. D., Spasojevic, I., Yang, J., Kinzler, K. W., … Yan, H. (2011). Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci U S A, 108(8), 3270–3275. https://doi.org/10.1073/pnas.1019393108
Reitman, Zachary J., Genglin Jin, Edward D. Karoly, Ivan Spasojevic, Jian Yang, Kenneth W. Kinzler, Yiping He, Darell D. Bigner, Bert Vogelstein, and Hai Yan. “Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.Proc Natl Acad Sci U S A 108, no. 8 (February 22, 2011): 3270–75. https://doi.org/10.1073/pnas.1019393108.
Reitman ZJ, Jin G, Karoly ED, Spasojevic I, Yang J, Kinzler KW, et al. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3270–5.
Reitman, Zachary J., et al. “Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.Proc Natl Acad Sci U S A, vol. 108, no. 8, Feb. 2011, pp. 3270–75. Pubmed, doi:10.1073/pnas.1019393108.
Reitman ZJ, Jin G, Karoly ED, Spasojevic I, Yang J, Kinzler KW, He Y, Bigner DD, Vogelstein B, Yan H. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3270–3275.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 22, 2011

Volume

108

Issue

8

Start / End Page

3270 / 3275

Location

United States

Related Subject Headings

  • Oligodendroglioma
  • Mutation
  • Metabolome
  • Isocitrate Dehydrogenase
  • Humans
  • Glutarates
  • Glioma
  • Dipeptides
  • Cell Line, Tumor