Mutant isocitrate dehydrogenase (mIDH)

Mutant isocitrate dehydrogenase (mIDH) refers to the oncogenic forms of the enzymes isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), which are critical drivers in the pathogenesis of various cancers, particularly low-grade gliomas and secondary glioblastomas [1, 4, 5]. In healthy cells, wild-type IDH1 (cytosolic) and IDH2 (mitochondrial) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) while generating NADPH [1, 7, 12]. Somatic mutations at specific arginine residues (e.g., IDH1 R132, IDH2 R172) confer a neomorphic gain-of-function that enables the enzyme to convert α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG) [1, 4, 7, 12]. The resulting accumulation of 2-HG competitively inhibits α-KG-dependent dioxygenases, leading to profound epigenetic dysregulation through DNA and histone hypermethylation, which blocks cellular differentiation and promotes tumorigenesis [4, 8, 11, 12]. Therapeutic targeting of mIDH with small-molecule inhibitors like vorasidenib and ivosidenib aims to reduce 2-HG levels, thereby reversing the differentiation block and slowing tumor growth [3, 6, 9, 13, 15]. These inhibitors have transformed the treatment landscape for IDH-mutant gliomas, offering a targeted approach that can delay the need for more aggressive therapies such as radiation and chemotherapy [15, 16, 18]. Clinical monitoring of these therapies involves tracking 2-HG levels and assessing liver function, as hepatotoxicity is a known safety concern [18, 21, 23].

Other names

Isocitrate dehydrogenase 1Isocitrate dehydrogenase 2IDH1IDH2NADP(+)-specific isocitrate dehydrogenaseMutant IDH1Mutant IDH2

Competitive inhibition of the mutant isocitrate dehydrogenase enzyme's active site, which prevents 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 [3, 6, 9, 13, 15].