Isocitrate dehydrogenase [NADP], mitochondrial R140Q mutant (IDH2 R140Q) (IDH2 R140Q)

Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial enzyme that normally catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) [1]. The R140Q mutation is a common somatic gain-of-function mutation that alters the enzyme's substrate specificity, leading to the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG) instead of α-KG [3,4]. Elevated 2-HG levels competitively inhibit α-KG-dependent enzymes, such as DNA methyltransferases and histone demethylases, resulting in epigenetic hypermethylation and a block in hematopoietic differentiation [4]. This molecular pathology is a key driver in approximately 10-15% of acute myeloid leukemia (AML) cases [3]. The IDH2 R140Q homodimer is the primary target of enasidenib, an oral, selective, small-molecule allosteric inhibitor [2]. By binding to the dimer interface, enasidenib stabilizes the enzyme in an open conformation, thereby reducing 2-HG production and inducing the differentiation of malignant blasts into mature functional cells [2,3].

Other names

Mutant IDH2 R140QmIDH2 R140QIsocitrate dehydrogenase 2 R140QIDH2 R140Q homodimer

Allosteric inhibition of the mutant IDH2 enzyme, preventing the conversion of alpha-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate.