Isocitrate dehydrogenase [NADP] cytoplasmic (mutant forms) (IDH1)

Isocitrate dehydrogenase 1 (IDH1) is a cytosolic enzyme that normally catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) while producing NADPH [1, 4]. Somatic mutations in IDH1, most frequently occurring at the arginine 132 (R132) residue, confer a neomorphic gain-of-function activity that converts α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG) [3]. The accumulation of 2-HG competitively inhibits α-KG-dependent dioxygenases, leading to DNA and histone hypermethylation, which blocks cellular differentiation and promotes oncogenesis [3, 4]. These mutations are characteristic of several malignancies, including acute myeloid leukemia (AML), low-grade gliomas, and cholangiocarcinoma [2, 6]. Targeted therapies such as ivosidenib and olutasidenib are small-molecule inhibitors designed to selectively bind the mutant enzyme and lower 2-HG levels, thereby inducing the differentiation of malignant cells [2, 5]. While effective, these treatments require careful monitoring for adverse events like differentiation syndrome and QT prolongation [2, 5].

Other names

IDH1IDCDIDPCPICDNADP(+)-specific isocitrate dehydrogenase, cytosolicIsocitrate dehydrogenase 1

Selective inhibition of the mutant IDH1 enzyme to block the neomorphic conversion of alpha-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (2-HG), thereby reducing 2-HG levels and restoring normal epigenetic signaling and cellular differentiation [2, 3, 5, 6].