Together with its mitochondria-localized isoform, IDH2, the IDH-encoding genes are the most frequently mutated metabolic genes associated with cancer (15, 16), with active site substitutions in IDH1 and IDH2 resulting in a gain of function (“neomorphic”) activity: i.e., catalysis of the reduction of 2OG to the oncometabolite 2-hydroxyglutarate (2HG) using NADPH (Scheme 1C) with a decrease in isocitrate oxidation efficiency (17). This evidence concerns the gene IDH2 and cancer.