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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Protein Data Bank
R132H mutant IDH1 structure files are deposited in the Protein Data Bank under accession code 3INM.
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.
This file contains Supplementary Figures 1-5 with Legends and Supplementary Tables 1-2.
About this article
Acta Neuropathologica Communications (2018)