Isocitrate dehydrogenase 1 and Isocitrate dehydrogenase 2 (mutant) (IDH1 (mutant), IDH2 (mutant))

Mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) refers to specific, recurrent cancer-associated amino acid substitutions in the IDH1 (cytosolic/peroxisomal) and IDH2 (mitochondrial) metabolic enzymes, most commonly at residues R132 (IDH1), R140 or R172 (IDH2)[7][8]. These mutations confer a neomorphic (new) enzymatic activity: instead of converting isocitrate to α-ketoglutarate as in their wild-type state, the mutant enzymes catalyze the reduction of α-ketoglutarate to D-2-hydroxyglutarate (D-2-HG), an oncometabolite[2][4][5][8]. Elevated D-2-HG inhibits α-ketoglutarate–dependent dioxygenases, disrupts DNA and histone demethylation, and broadly alters cellular epigenetic state, promoting tumorigenesis through blocked differentiation and other mechanisms[2][4][6][8]. These mutations are particularly frequent in lower-grade gliomas, secondary glioblastomas, acute myeloid leukemia, and chondrosarcoma, and are a major therapeutic target. Multiple small-molecule inhibitors of mutant IDH1 and IDH2 are approved or in development for cancer therapy, especially in AML and astrocytoma[4]. Measurement of D-2-HG and mutation status serve as both diagnostic and response biomarkers, but treatment with inhibitors can be associated with differentiation syndrome and other class effects[4]. The mutant forms are considered distinct from their wild-type counterparts for therapeutic, diagnostic, and biological classification.

Other names

Mutant IDH1Mutant IDH2IDH1 R132H (common mutant allele)IDH2 R140Q, IDH2 R172K (common mutant alleles)Neomorphic IDH1/2

Competitive inhibition of mutant IDH1 or IDH2 enzymatic activity, reducing D-2-hydroxyglutarate production Restoration of normal epigenetic regulation and cell differentiation