Isocitrate dehydrogenase 2 (NADP+), mitochondrial (IDH2)

Isocitrate dehydrogenase 2 (NADP+), mitochondrial (IDH2) is an enzyme localized to the mitochondria and catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), producing NADPH. This reaction is crucial for cellular metabolism, energy production, and maintaining redox homeostasis. Mutations in IDH2 (commonly at residues R140 or R172) confer a neomorphic enzymatic function: instead of generating α-KG, the mutant enzyme reduces α-KG to the oncometabolite 2-hydroxyglutarate (2-HG)[1][2][3][4][5]. Accumulation of 2-HG leads to broad epigenetic dysregulation by inhibiting α-KG-dependent dioxygenases, such as TET and JMJ demethylases, resulting in hypermethylation of DNA and histones, impaired cellular differentiation, and oncogenesis—particularly in myeloid malignancies and gliomas[2][3][4][5]. Targeting mutated IDH2 with selective inhibitors (such as enasidenib) is an established therapeutic strategy in IDH2-mutant cancers[5]. The presence of IDH2 mutations and elevated 2-HG serves as both a disease biomarker and a patient selection tool for targeted therapies[2][5]. Safety concerns for IDH2-targeting therapies primarily involve differentiation syndrome and possible interference with other metabolic and epigenetic processes[5].

Other names

IDH2Isocitrate dehydrogenase [NADP] 2mIDH2 (for "mutant IDH2" in literature)

Inhibition of neomorphic (mutant) IDH2 enzyme activity (prevents conversion of α-KG to 2-HG)