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Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

An Addendum to this article was published on 17 June 2010

Abstract

Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme’s ability to catalyse conversion of isocitrate to α-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert α-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.

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Figure 1: Cells expressing human R132H IDH1 contain markedly elevated levels of 2HG.
Figure 2: R132H mutation in IDH1 results in production of R (−)-2HG.
Figure 3: Structural analysis of R132H mutant IDH1.
Figure 4: Human malignant gliomas containing R132 mutations in IDH1 contain increased concentrations of 2HG.

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Protein Data Bank

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R132H mutant IDH1 structure files are deposited in the Protein Data Bank under accession code 3INM.

References

  1. Balss, J. et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 116, 597–602 (2008)

    CAS  Article  Google Scholar 

  2. Watanabe, T., Nobusawa, S., Kleihues, P. & Ohgaki, H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am. J. Pathol. 174, 1149–1153 (2009)

    CAS  Article  Google Scholar 

  3. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009)

    CAS  Article  Google Scholar 

  4. Hartmann, C. et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 118, 469–474 (2009)

    Article  Google Scholar 

  5. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008)

    ADS  CAS  Article  Google Scholar 

  6. Bleeker, F. E. et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum. Mutat. 30, 7–11 (2009)

    CAS  Article  Google Scholar 

  7. Zhao, S. et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324, 261–265 (2009)

    ADS  CAS  Article  Google Scholar 

  8. Lu, W., Kimball, E. & Rabinowitz, J. D. A high-performance liquid chromatography-tandem mass spectrometry method for quantitation of nitrogen-containing intracellular metabolites. J. Am. Soc. Mass Spectrom. 17, 37–50 (2006)

    CAS  Article  Google Scholar 

  9. Struys, E. A., Jansen, E. E., Verhoeven, N. M. & Jakobs, C. Measurement of urinary d- and l-2-hydroxyglutarate enantiomers by stable-isotope-dilution liquid chromatography-tandem mass spectrometry after derivatization with diacetyl-l-tartaric anhydride. Clin. Chem. 50, 1391–1395 (2004)

    CAS  Article  Google Scholar 

  10. Xu, X. et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J. Biol. Chem. 279, 33946–33957 (2004)

    CAS  Article  Google Scholar 

  11. Aktas, D. F. & Cook, P. F. A lysine-tyrosine pair carries out acid-base chemistry in the metal ion-dependent pyridine dinucleotide-linked β-hydroxyacid oxidative decarboxylases. Biochemistry 48, 3565–3577 (2009)

    CAS  Article  Google Scholar 

  12. Struys, E. A. et al. Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am. J. Hum. Genet. 76, 358–360 (2005)

    CAS  Article  Google Scholar 

  13. Kölker, S., Mayatepek, E. & Hoffmann, G. F. White matter disease in cerebral organic acid disorders: clinical implications and suggested pathomechanisms. Neuropediatrics 33, 225–231 (2002)

    Article  Google Scholar 

  14. Wajner, M., Latini, A., Wyse, A. T. & Dutra-Filho, C. S. The role of oxidative damage in the neuropathology of organic acidurias: insights from animal studies. J. Inherit. Metab. Dis. 27, 427–448 (2004)

    CAS  Article  Google Scholar 

  15. Aghili, M., Zahedi, F. & Rafiee, E. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J. Neurooncol. 91, 233–236 (2009)

    Article  Google Scholar 

  16. Kolker, S. et al. NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria. Eur. J. Neurosci. 16, 21–28 (2002)

    Article  Google Scholar 

  17. Latini, A. et al. d-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats. Eur. J. Neurosci. 17, 2017–2022 (2003)

    Article  Google Scholar 

  18. Tsacopoulos, M. Metabolic signaling between neurons and glial cells: a short review. J. Physiol. (Paris) 96, 283–288 (2002)

    CAS  Article  Google Scholar 

  19. Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009)

    CAS  Article  Google Scholar 

  20. Luo, B., Groenke, K., Takors, R., Wandrey, C. & Oldiges, M. Simultaneous determination of multiple intracellular metabolites in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle by liquid chromatography-mass spectrometry. J. Chromatogr. A 1147, 153–164 (2007)

    CAS  Article  Google Scholar 

  21. Munger, J. et al. Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nature Biotechnol. 26, 1179–1186 (2008)

    CAS  Article  Google Scholar 

  22. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode (HKL2000). Methods Enzymol. 276, 307–326 (1997)

    CAS  Article  Google Scholar 

  23. McCoy, A. J. et al. Phaser Crystallographic Software. J. Appl. Cryst. 40, 658–674 (2007)

    CAS  Article  Google Scholar 

  24. Emsley, P. & Cowtan, K. COOT: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)

    Article  Google Scholar 

  25. Collaborative Computational Project, Number 4. The CCP4 Suite: Programs for Protein Crystallography. Acta Crystallogr. D 50, 760–763 (1994)

  26. DeLano, W. L. The PyMOL Molecular Graphics System (DeLano Scientific, 2002)

    Google Scholar 

Download references

Acknowledgements

We thank R. K. Suto, R. S. Brown and E. Fontano at Xtal BioStructures for performing crystallographic studies, and S. Wang at ChemPartner for assistance with biochemical experiments. We thank G. Petsko for his review of the structure data. We also thank T. Mak, N. Wu, L. Tartaglia, J. Saunders, F. Salituro and D. Schenkein for discussions and/or comments on the manuscript. Asterand, PLC provided some of the glioma specimens and SeqWright Inc. assisted with genomic DNA SNP analysis. J.D.R. is supported by NIH R21 CA128620.

Author Contributions L.D., D.W.W., S.G., B.D.B., M.A.B., E.M.D., V.R.F., H.G.J., S.J., M.C.K., K.M.M., R.M.P., P.S.W., K.E.Y., J.D.R., L.M.L. and S.M.S. contributed extensively to the work presented in this paper. L.C.C., C.B.T., M.G.V.H. and S.M.S. provided support and conceptual advice. L.D., M.G.V.H. and S.M.S. wrote the manuscript.

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Correspondence to Shinsan M. Su.

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L.D., D.W.W., S.G., M.A.B., E.M.D., V.R.F., H.G.J., S.J., M.C.K., K.M.M., K.E.Y., J.D.R., L.C.C, C.B.T., M.G.V.H. and S.M.S. are employees or consultants of Agios Pharmaceuticals and have financial interest in Agios.

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Dang, L., White, D., Gross, S. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). https://doi.org/10.1038/nature08617

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