Isocitrate dehydrogenase 2 (NADP+), mitochondrial R172K mutant (IDH2 R172K)

Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial enzyme that normally catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) in the tricarboxylic acid cycle (PMID: 20171147). The R172K mutation is a recurrent somatic alteration in the enzyme's active site that confers a neomorphic gain-of-function, allowing the enzyme to convert α-KG into the oncometabolite (R)-2-hydroxyglutarate (2-HG) (PMID: 20171147, 21326614). Elevated levels of 2-HG competitively inhibit α-KG-dependent dioxygenases, such as TET2 DNA hydroxylases and JmjC histone demethylases, leading to global DNA and histone hypermethylation (PMID: 20171147, 25043045). This epigenetic dysregulation blocks cellular differentiation and promotes oncogenesis in various malignancies, including acute myeloid leukemia (AML), angioimmunoblastic T-cell lymphoma (AITL), and chondrosarcoma (PMID: 20567020, 33017591). Therapeutic targeting of the IDH2 R172K mutant is achieved through selective allosteric inhibitors like enasidenib (AG-221) (PMID: 28193778). These inhibitors bind to the mutant enzyme to suppress 2-HG production, thereby restoring normal epigenetic signaling and inducing the differentiation of malignant cells into mature, functional cells (PMID: 28588020).

Other names

IDH2 R172KMutant IDH2Isocitrate dehydrogenase [NADP], mitochondrial R172K

Allosteric inhibition of mutant IDH2 enzyme to reduce 2-hydroxyglutarate production and promote cellular differentiation.