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

Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial enzyme that normally catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) while reducing NADP+ to NADPH [1, 2]. In various cancers, somatic mutations (most commonly at residues R140 and R172) confer a neomorphic gain-of-function activity, leading to the reduction of α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG) [3, 5]. The accumulation of 2-HG competitively inhibits α-KG-dependent dioxygenases, such as TET2 DNA demethylases and Jumonji-C domain-containing histone demethylases, resulting in DNA and histone hypermethylation and a subsequent block in cellular differentiation [1, 3]. This metabolic reprogramming is a key driver in the pathogenesis of acute myeloid leukemia (AML), gliomas, and other malignancies [2, 5]. Targeted inhibitors like enasidenib bind to the mutant IDH2 enzyme to suppress 2-HG production, thereby inducing the differentiation of malignant cells into mature, functional cells [3, 4]. Clinical use of these inhibitors requires monitoring for differentiation syndrome, a potentially fatal complication characterized by rapid expansion of maturing myeloid cells [4]. Additionally, IDH2 mutations are used as critical biomarkers for patient stratification and prognostic assessment in hematologic and solid tumors [5].

Other names

IDH2D2HGA2ICD-MIDHMIDPIDPMmNADP-IDHIsocitrate dehydrogenase (NADP(+)) 2, mitochondrialNADP(+)-specific ICDHMutant isocitrate dehydrogenase 2

Allosteric inhibition of the mutant enzyme to reduce production of the oncometabolite D-2-hydroxyglutarate (2-HG) and restore cellular differentiation.