Mutant isocitrate dehydrogenase 1 and 2 (Mutant IDH1/2)

Mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) are metabolic enzymes that acquire a neomorphic gain-of-function due to specific somatic point mutations, most commonly at arginine residues such as IDH1 R132, IDH2 R140, or IDH2 R172 [2, 10]. While wild-type IDH enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate (α-KG), the mutant forms reduce α-KG to the oncometabolite D-2-hydroxyglutarate (2-HG) [3, 8]. The resulting accumulation of 2-HG competitively inhibits α-KG-dependent dioxygenases, including TET DNA demethylases and JmjC histone demethylases, which leads to epigenetic hypermethylation and a block in cellular differentiation [5, 10]. These mutations are key drivers in several malignancies, including acute myeloid leukemia (AML), low-grade gliomas, secondary glioblastomas, and cholangiocarcinoma [2, 14]. Therapeutic strategies focus on small-molecule inhibitors like ivosidenib, enasidenib, and vorasidenib, which bind to the mutant enzymes to suppress 2-HG production and restore normal cellular differentiation [6, 18]. Clinical use of these inhibitors has shown significant efficacy in improving progression-free survival and inducing clinical responses, though challenges such as differentiation syndrome and potential hepatotoxicity remain [15, 19].

Other names

IDH1 mutantIDH2 mutantmIDH1mIDH2Isocitrate dehydrogenase (NADP+) 1/2 mutantR132H IDH1R140Q IDH2R172K IDH2

Competitive inhibition of the mutant enzyme's active site to prevent 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 regulation and cellular differentiation [5, 10].