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

Isocitrate dehydrogenase [NADP], mitochondrial (IDH2) is a key metabolic enzyme that normally catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) in the mitochondria (UniProt: P48735). The R140Q mutation is a common somatic alteration, particularly in hematologic malignancies, that confers a neomorphic gain-of-function (PMID: 20171147). This mutant enzyme acquires the ability to convert α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG) (PMID: 23264629). Elevated levels of 2-HG competitively inhibit α-KG-dependent dioxygenases, such as histone demethylases and TET DNA hydroxylases, leading to global DNA and histone hypermethylation (PMID: 28588020). This epigenetic dysregulation results in a block of cellular differentiation, promoting the development and maintenance of cancers like acute myeloid leukemia (AML) (PMID: 28193778). Targeted inhibitors like enasidenib bind allosterically to the mutant enzyme to reduce 2-HG production and restore normal differentiation pathways (FDA: Idhifa Prescribing Information).

Other names

IDH2 R140QIsocitrate dehydrogenase 2 R140QmIDH2 R140QIDH2 R140Q mutant

Enasidenib is an allosteric inhibitor that binds to the IDH2 R140Q mutant enzyme, stabilizing its open conformation and preventing the neomorphic conversion of alpha-ketoglutarate to the oncometabolite 2-hydroxyglutarate (PMID: 28193778). This reduction in 2-hydroxyglutarate levels reverses the epigenetic block on cellular differentiation, allowing leukemic blasts to mature into functional myeloid cells (PMID: 28588020).