Isocitrate dehydrogenase 2, mitochondrial (IDH2) (IDH2)

Isocitrate dehydrogenase 2, mitochondrial (IDH2) is a metabolic enzyme that facilitates the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (a-KG) within the mitochondria, generating NADPH in the process (UniProt: P48735). It is essential for the tricarboxylic acid (TCA) cycle and maintaining the cellular antioxidant defense system (PubMed: 23541361). Somatic mutations in the IDH2 gene, particularly at the R140 and R172 positions, are frequently observed in patients with acute myeloid leukemia (AML) and certain solid tumors like gliomas (PubMed: 20035030). These mutations grant the enzyme a neomorphic function, allowing it to convert a-KG into the oncometabolite (R)-2-hydroxyglutarate (2-HG), which disrupts epigenetic regulation by inhibiting a-KG-dependent dioxygenases (PubMed: 23334322). This epigenetic dysregulation leads to a block in hematopoietic or cellular differentiation, contributing to oncogenesis (PubMed: 28783719). Targeted inhibitors such as enasidenib have been developed to specifically block the mutant IDH2 enzyme, thereby reducing 2-HG levels and allowing malignant cells to resume normal differentiation (FDA: Idhifa Prescribing Information).

Other names

Isocitrate dehydrogenase [NADP], mitochondrialIDPIDHMNADP(+)-specific mitochondrial isocitrate dehydrogenaseOxalosuccinate decarboxylaseICD-M

Small molecule inhibition of mutant IDH2 enzyme variants to suppress the production of the oncometabolite (R)-2-hydroxyglutarate, thereby reversing epigenetic dysregulation and inducing cellular differentiation.