Isocitrate dehydrogenase 1 (NADP+), soluble (R132H mutant) (IDH1 R132H)

Mutant isocitrate dehydrogenase 1 (IDH1), specifically the R132H variant, is a metabolic enzyme that plays a critical role in the pathogenesis of several cancers, including gliomas and acute myeloid leukemia (AML) [1.1.1, 1.3.1]. In its normal state, wild-type IDH1 catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) while producing NADPH [1.1.1, 1.2.1]. The R132H mutation, which involves a substitution of arginine with histidine at codon 132, confers a neomorphic gain-of-function that enables the enzyme to convert α-KG into the oncometabolite D-2-hydroxyglutarate (D-2-HG) [1.2.1, 1.3.3]. The accumulation of D-2-HG competitively inhibits α-KG-dependent dioxygenases, leading to widespread epigenetic dysregulation through DNA and histone hypermethylation [1.1.3, 1.2.2]. This epigenetic shift blocks cellular differentiation and promotes a pro-tumorigenic environment [1.3.1, 1.4.3]. Therapeutic strategies focus on small-molecule inhibitors, such as ivosidenib and vorasidenib, which selectively bind to the mutant enzyme to suppress D-2-HG production and restore normal cellular maturation [1.4.1, 1.4.4]. These inhibitors have shown clinical efficacy in reducing tumor burden and improving survival in patients with IDH1-mutated malignancies [1.4.1, 1.4.3].

Other names

IDH1PICDIDPIDPCCytosolic NADP-isocitrate dehydrogenaseIsocitrate dehydrogenase [NADP] cytoplasmic

Selective inhibition of the mutant IDH1 enzyme's neomorphic activity to reduce the production of the oncometabolite D-2-hydroxyglutarate (D-2-HG), thereby reversing the differentiation block and epigenetic dysregulation [1.3.1, 1.4.3].