Isocitrate dehydrogenase 1, mutant form (mutant IDH1)

Mutant isocitrate dehydrogenase 1 refers specifically to cancer-associated forms of the enzyme encoded by the IDH1 gene, most commonly involving mutation of the arginine-132 residue (e.g., R132H, R132C) [7]. While the wild-type enzyme normally catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) in the cytosol and peroxisome, mutant IDH1 acquires a novel (neomorphic) activity, producing the oncometabolite D-2-hydroxyglutarate (2-HG) from α-KG using NADPH [2][7]. Accumulation of 2-HG leads to widespread epigenetic changes including hypermethylation of DNA and histones, altered DNA damage response, and dysregulation of cellular differentiation, contributing to oncogenesis—especially in gliomas and certain leukemias [6][2][7]. Mutant IDH1 is now a validated therapeutic target, and specific inhibitors (e.g., ivosidenib, vorasidenib) are being developed for tumors harboring these mutations, with ongoing efforts to refine patient selection using biomarkers such as elevated 2-HG and mutant protein detection [7]. Safety concerns include off-target effects, impacts on normal metabolism, and the need to avoid inhibition of wild-type IDH1, which is vital for cellular homeostasis.

Other names

IDH1 mutantMutant isocitrate dehydrogenase 1IDH1 R132H (specific mutation variant)IDH1 R132C (specific mutation variant)IDH1 R132G (specific variant)Mutant IDH

Inhibition of mutant IDH1 enzyme (blocks production of D-2-hydroxyglutarate). Restoration of normal cellular metabolism and epigenetic regulation. Modulation of histone and DNA methylation. Sensitization of cancer cells to chemotherapy and radiotherapy by influencing DNA damage response.