Isocitrate dehydrogenase [NADP], mitochondrial (IDH2)

Isocitrate dehydrogenase [NADP], mitochondrial (IDH2) is a key metabolic enzyme located in the mitochondrial matrix that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) as part of the tricarboxylic acid (TCA) cycle [7, 11]. This reaction is coupled with the reduction of NADP+ to NADPH, which is essential for maintaining cellular redox homeostasis and protecting against oxidative stress [11, 12]. Somatic gain-of-function mutations in IDH2, most commonly at residues R140 and R172, result in a neomorphic activity that converts α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG) [2, 15]. The accumulation of 2-HG competitively inhibits α-KG-dependent dioxygenases, leading to DNA and histone hypermethylation, which blocks normal cellular differentiation and promotes oncogenesis in diseases such as acute myeloid leukemia (AML) and glioma [3, 9, 13]. Therapeutic targeting of mutant IDH2 with small-molecule inhibitors like enasidenib reduces 2-HG levels, thereby alleviating the differentiation block and allowing malignant cells to mature [1, 5]. These inhibitors have become a cornerstone of precision medicine for patients with relapsed or refractory IDH2-mutated AML [5, 10].

Other names

IDH2ICD-MIDPNADP(+)-specific ICDHOxalosuccinate decarboxylaseD2HGA2IDHMmNADP-IDH

Selective allosteric inhibition of mutant IDH2 enzymes to reduce the production of the oncometabolite 2-hydroxyglutarate (2-HG) and restore normal cellular differentiation [1, 2, 3].