Isocitrate dehydrogenase 1 (mutant) (IDH1 (mutant))

Mutant isocitrate dehydrogenase 1 (IDH1) is a cytoplasmic and peroxisomal enzyme that, when mutated—most commonly at residue arginine 132—acquires a neomorphic activity, catalyzing the NADPH-dependent reduction of α-ketoglutarate (α-KG) to D-2-hydroxyglutarate (D2HG), a metabolite implicated in oncogenesis[3][6][8]. The mutant enzyme disrupts normal metabolic and epigenetic regulation, leading to impaired cell differentiation and driving tumorigenesis in several malignancies including low grade glioma, secondary glioblastoma, and acute myeloid leukemia[5][6][8]. Drugs targeting mutant IDH1, such as ivosidenib, inhibit this aberrant activity, lowering D2HG, and enabling partial restoration of cellular differentiation. The measurement of D2HG levels and detection of specific IDH1 mutations serve as biomarkers for diagnosis and therapeutic response, though treatment with IDH1 inhibitors can be associated with unique toxicities such as differentiation syndrome and liver enzyme abnormalities[5][8].

Other names

IDH1 mutantmutant IDH1R132H IDH1isocitrate dehydrogenase 1 mutatedIDH1 R132CIDH1 R132SIDH1 R132GIDH1 R132L

Competitive inhibition of mutant IDH1 enzyme activity (e.g., ivosidenib binds to the mutant enzyme and inhibits its neomorphic function). Reduction in D-2-hydroxyglutarate (D2HG) oncometabolite levels. Restoration of normal cellular differentiation and epigenetic status.