Isocitrate dehydrogenase 1 (NADP+), soluble (mutant form) (IDH1 (mutant))

Mutant IDH1 R132 refers to a specific oncogenic variant of the isocitrate dehydrogenase 1 enzyme, characterized by a mutation at the arginine 132 residue, such as R132H or R132C. In its wild-type state, IDH1 catalyzes the conversion of isocitrate to alpha-ketoglutarate (α-KG) while producing NADPH. However, the R132 mutation confers a neomorphic gain-of-function that allows the enzyme to reduce α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG). The resulting accumulation of 2-HG competitively inhibits α-KG-dependent dioxygenases, including TET DNA demethylases and Jumonji-family histone demethylases. This inhibition leads to global DNA and histone hypermethylation, which blocks normal cellular differentiation and drives the development of various cancers, such as acute myeloid leukemia (AML) and low-grade gliomas. Therapeutic targeting of mutant IDH1 involves small-molecule inhibitors like ivosidenib and vorasidenib, which selectively bind to the mutant enzyme to suppress 2-HG production. By lowering 2-HG levels, these drugs aim to reverse the epigenetic block, thereby inducing the differentiation of malignant cells into mature, non-proliferative states.

Other names

mIDH1IDH1 R132HIDH1 R132CIsocitrate dehydrogenase [NADP] cytoplasmic (mutant)NADP(+)-specific isocitrate dehydrogenase, cytosolic (mutant)

Small molecule inhibition of the mutant IDH1 enzyme to reduce production of the oncometabolite 2-hydroxyglutarate (2-HG), thereby reversing epigenetic hypermethylation and restoring normal cellular differentiation.