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

Isocitrate dehydrogenase [NADP+] 2, mitochondrial (IDH2) is a key metabolic enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) while reducing NADP+ to NADPH [UniProt: P48735]. Located within the mitochondrial matrix, it plays a vital role in the tricarboxylic acid (TCA) cycle and the maintenance of cellular redox homeostasis. Somatic gain-of-function mutations in the IDH2 gene, particularly at the R140 and R172 residues, confer a neomorphic activity that converts α-KG into the oncometabolite (R)-2-hydroxyglutarate (2-HG) [PubMed: 23434737]. The accumulation of 2-HG leads to competitive inhibition of α-KG-dependent dioxygenases, resulting in global DNA and histone hypermethylation and a subsequent block in cellular differentiation [PubMed: 20145208]. These mutations are frequently identified in patients with acute myeloid leukemia (AML), gliomas, and chondrosarcomas. Therapeutic targeting of mutant IDH2 with small-molecule inhibitors, such as enasidenib, has proven effective in lowering 2-HG levels and inducing clinical responses by promoting the differentiation of malignant cells [FDA: Enasidenib Prescribing Information].

Other names

IDPICD-MmIDH2Isocitrate dehydrogenase 2 (NADP+), mitochondrialNADP+-specific isocitrate dehydrogenase, mitochondrialOxalosuccinate decarboxylase

Allosteric inhibition of mutant IDH2 enzymes to prevent the neomorphic conversion of alpha-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate (2-HG), thereby restoring normal epigenetic signaling and cellular differentiation.