Isocitrate dehydrogenase 1 (NADP+), cytoplasmic (IDH1)

Isocitrate dehydrogenase 1 (IDH1) is a key metabolic enzyme located in the cytoplasm and peroxisomes that catalyzes the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), producing NADPH in the process. This reaction is vital for maintaining cellular antioxidant defenses and supporting lipid biosynthesis. In various cancers, somatic mutations in the IDH1 gene (most frequently at the R132 residue) grant the enzyme a neomorphic gain-of-function, allowing it to reduce α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG). The accumulation of 2-HG competitively inhibits α-KG-dependent dioxygenases, leading to DNA and histone hypermethylation, which blocks cellular differentiation and promotes tumorigenesis. Consequently, IDH1 has emerged as a major therapeutic target, particularly in acute myeloid leukemia (AML) and low-grade gliomas. Targeted inhibitors like ivosidenib and olutasidenib are designed to lower 2-HG levels and induce the differentiation of malignant cells into mature, functional cells.

Other names

Isocitrate dehydrogenase [NADP] cytoplasmicIDPIDPCPICDNADP-dependent isocitrate dehydrogenase, cytosolicOxalosuccinate decarboxylase

Small molecule inhibition of the mutant IDH1 enzyme to prevent the neomorphic conversion of alpha-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG).