Isocitrate dehydrogenase [NADP], mitochondrial (IDH2) (IDH2)

Wild-type Isocitrate dehydrogenase [NADP], mitochondrial (IDH2) is a key metabolic enzyme that functions as a homodimer within the mitochondrial matrix. It plays a central role in the tricarboxylic acid (TCA) cycle by catalyzing the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), a process coupled with the reduction of NADP+ to NADPH [UniProt: P48735]. This activity is crucial for maintaining cellular redox states and providing intermediates for various biosynthetic pathways. While somatic gain-of-function mutations in IDH2 (most commonly R140 and R172) are well-characterized drivers in acute myeloid leukemia (AML) and gliomas due to the production of the oncometabolite 2-hydroxyglutarate (2-HG), the wild-type enzyme is essential for normal cellular physiology [PubMed: 23817019]. Therapeutic development has largely focused on mutant-selective inhibitors, such as enasidenib, to specifically target malignant cells while sparing the vital functions of the wild-type homodimer [FDA: IDHIFA Label]. However, emerging research suggests that wild-type IDH2 may be overexpressed in certain non-mutated cancers to support metabolic adaptation, presenting a complex landscape for therapeutic intervention [PubMed: 30107172]. Inhibition of the wild-type enzyme is generally avoided in clinical practice due to the risk of disrupting mitochondrial respiration and increasing oxidative stress [PubMed: 28743684].

Other names

IDPIDHMmNADP-IDHIsocitrate dehydrogenase 2NADP(+)-specific mitochondrial isocitrate dehydrogenase

Catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) and CO2, reducing NADP+ to NADPH.