Figure 2

Impact of IDH1/2 mutations on tumor cell biology. (a) In normal cells, the role of IDH1 and IDH2 enzymes is to convert isocitrate to α-ketoglutarate (α-KG), converting NADP+ to NADPH. The presence of α-KG regulates prolylhydroxylases (PHD) that, in turn, promote the degradation of hypoxia-inducible factor 1α (HIF-1α). HIF-1α is a transcription factor that regulates the expression of genes related to glucose metabolism, angiogenesis, and other signaling pathways by sensing low cellular oxygen levels. The mutant IDH enzymes convert α-KG to 2-hydroxyglutarate (2-HG), leading to the build up of this oncometabolite. (b) Comparison of metabolomic profiling of IDH wild-type (upper panel) and mutant (lower panel) cells, indicating the increased levels of 2-HG associated with the mutation. 2-HG is absent in IDH wild-type cells. Panel (b) reproduced with permission from [15].