Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

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