Isocitrate dehydrogenase 1 mutant enzyme (IDH1 mutant (or mIDH1))

Isocitrate dehydrogenase 1 mutant enzymes are altered forms of the cytosolic enzyme IDH1, which normally catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate using NADP+ as a cofactor[1][7]. The most recognized oncogenic mutation occurs at arginine 132 (R132), frequently substituted by histidine (R132H), lysine, or cysteine, resulting in the enzyme acquiring a neomorphic activity: the NADPH-dependent reduction of α-ketoglutarate to D-2-hydroxyglutarate (2-HG)[2][3][4][5]. Elevated intracellular 2-HG acts as an oncometabolite, competitively inhibiting α-ketoglutarate–dependent dioxygenases involved in epigenetic regulation, blocking differentiation, and promoting tumorigenesis, notably in gliomas and acute myeloid leukemia[3][4][5][6]. These mutant enzymes are highly targeted in oncology for their unique pathological role, and several small molecule inhibitors have been developed that selectively bind and inhibit the mutant, but not the wild-type, enzyme[2][3][6][9]. FDA-approved drugs like Ivosidenib have demonstrated clinical efficacy and acceptable safety profiles in patients with IDH1-mutated cancers[3][9].

Other names

mutIDH1IDH1 R132H mutantMutant isocitrate dehydrogenase 1mIDH1

Allosteric inhibition of mutant IDH1 enzyme activity, reducing production of the oncometabolite D-2-hydroxyglutarate