Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

By L. Dang, D. White, Stefan Gross, Bryson D. Bennett, M. Bittinger, E. Driggers, V. Fantin, H. G. Jang, Shengfang Jin, M. Keenan and 10 more. Nature, 2009

4,048 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Genetics, Materials Chemistry

View Paper: https://www.semanticscholar.org/paper/d2cf3e93599561e919b1aa49734bead20075925d

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Citations in the corpus

Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases (2011, positive): “In IDH1 mutated glioma, D-2-HG accumulated to astonishingly high levels of 5–35 mmol/g of GBM (Dang et al., 2009), which could be equivalent to 5–35 mM assuming the tissue density of 1 g/ml.”
Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. (2011, background): “[28] Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin”
Otto Warburg's contributions to current concepts of cancer metabolism (2011, background): “Mutant IDH1 and IDH2 exhibit a neo-enzymatic activity: they convert α-ketoglutarate to 2-hydroxyglutarate(2-HG”
Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011, positive): “…al., 2009; Parsons et al., 2008; Ward et al., 2010; Yan et al., 2009) are mutually exclusive with TET2 mutations, and that production of 2-hydroxyglutarate by neomorphic IDH1/2 mutant proteins (Dang et al., 2009) inhibits TET2 catalytic activity (Fig- ueroa et al., 2010; Xu et al., 2011).”
Predicting the functional impact of protein mutations: application to cancer genomics (2011, background): “Here, we also consider a fourth type, ‘switch of function’, intermediate between (i) and (ii), such as the recently much studied mutations in IDH1 in glioblastoma and AML (44).”
The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate (2010, methodology): “This result is not unexpected, as a number of mutations of R132 to other residues have also been shown to accumulate 2HG in glioma samples (Dang et al., 2009).”
Targeting cancer metabolism: a therapeutic window opens (2011, background): “, and lead to the production of D -2-hydroxyglutarate (2HG) — a metabolite that is only found at very low levels in normal cell”