Isocitrate dehydrogenase 2 (NADP+), mitochondrial (R140 mutant) (IDH2 R140)

Mutant IDH2 R140 refers to a specific oncogenic variant of the mitochondrial enzyme isocitrate dehydrogenase 2 [1.1.3, 1.4.3]. In its wild-type form, IDH2 catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) as part of the tricarboxylic acid cycle [1.3.3, 1.4.1]. However, mutations at the R140 residue (most frequently R140Q) confer a neomorphic gain-of-function that enables the enzyme to reduce α-KG into the oncometabolite (R)-2-hydroxyglutarate (2-HG) [1.1.4, 1.2.1, 1.5.2]. The accumulation of 2-HG leads to the competitive inhibition of α-ketoglutarate-dependent dioxygenases, resulting in global DNA and histone hypermethylation [1.3.2, 1.3.5, 1.4.4]. This epigenetic shift blocks the normal differentiation of hematopoietic progenitor cells, driving the development of malignancies such as acute myeloid leukemia (AML) [1.3.1, 1.4.3, 1.5.3]. Therapeutic targeting of this mutant enzyme with allosteric inhibitors like enasidenib reduces 2-HG levels, thereby alleviating the differentiation block and promoting the maturation of leukemic blasts into functional myeloid cells [1.3.1, 1.3.3, 1.5.1].

Other names

IDH2 R140QmIDH2Isocitrate dehydrogenase [NADP], mitochondrial (R140 mutant)IDH2 R140

Enasidenib is a small-molecule allosteric inhibitor that binds to the mutant IDH2 dimer, preventing the conformational change required for the neomorphic conversion of alpha-ketoglutarate to 2-hydroxyglutarate [1.3.1, 1.3.3]. By lowering 2-HG levels, the drug reverses the inhibition of alpha-ketoglutarate-dependent dioxygenases, restoring normal epigenetic regulation and allowing for the differentiation of leukemic blasts into mature myeloid cells [1.3.2, 1.3.5].