Isocitrate dehydrogenase [NADP(+)] 1 (cytoplasmic) (IDH1)

Isocitrate dehydrogenase [NADP(+)] 1 (IDH1) is a cytosolic and peroxisomal enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (also called 2-oxoglutarate) with the concomitant reduction of NADP+ to NADPH, a pivotal reaction in the TCA cycle and cellular redox metabolism[1][3][7]. IDH1 is a homodimer with its active site at the interface between two subunits, allowing for intricate conformational regulation[1][9]. Physiologically, IDH1 supports redox homeostasis, lipid metabolism, and protection against oxidative stress, and regulates glucose-stimulated insulin secretion[1][3]. Mutations (particularly at Arg132, R132H) confer gain of function, producing the oncometabolite D-2-hydroxyglutarate from α-ketoglutarate, which disrupts cellular epigenetic and metabolic regulation, driving the development of multiple cancers, especially lower-grade gliomas and acute myeloid leukemia[7][9]. IDH1 (especially its mutant forms) is a validated therapeutic target, and several small-molecule inhibitors such as ivosidenib are approved or in development for IDH1-mutant malignancies. Key challenges in targeting IDH1 include drug resistance, differentiation syndrome, and safely modulating normal cellular metabolism[7].

Other names

Isocitrate dehydrogenase 1PICDIDHCytosolic NADP-isocitrate dehydrogenaseIDPcNADP(+)-specific ICDHOxalosuccinate decarboxylaseHEL-216HEL-S-26IDCDIDPCNADP-dependent isocitrate dehydrogenase, cytosolicNADP-dependent isocitrate dehydrogenase, peroxisomalepididymis luminal protein 216epididymis secretory protein Li 26epididymis secretory sperm binding proteinisocitrate dehydrogenase (NADP(+)) 1, soluble

Inhibition of mutant IDH1 enzymatic conversion of α-ketoglutarate to D-2-hydroxyglutarate (oncometabolite)