Fig. 1. Metabolic reactions catalyzed by wild-type and mutant isocitrate dehydrogenases (IDHs). IDH1/2/3 catalyzes the conversion of isocitrate (ICT) into α-ketoglutarate (α-KG). While, IDH1/2 utilizes NADP⁺ as a cofactor, IDH3 uses NAD⁺ instead. In particular, mutant IDH1/2 enzymes gain a new catalytic function that irreversibly converts α-KG into (R)-2-hydroxyglutarate (R-2HG), in which NADPH acts as a hydrogen donor and is oxidized into NADP⁺ .