Isocitrate dehydrogenase [NADP+] 1 (IDH1)

Isocitrate dehydrogenase [NADP+] 1 (IDH1) wild-type is a cytosolic and peroxisomal enzyme that catalyzes the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), a process coupled with the reduction of NADP+ to NADPH (UniProt: O75874). This reaction serves as a primary source of cytosolic NADPH, which is essential for maintaining cellular redox homeostasis by regenerating reduced glutathione and supporting reductive biosynthetic pathways, such as lipid synthesis (PubMed: 11564744, 15191851). While IDH1 is most frequently discussed in the context of gain-of-function mutations (e.g., R132H) that drive oncogenesis through the production of the oncometabolite D-2-hydroxyglutarate, the wild-type enzyme is increasingly recognized for its role in cancer cell survival (PubMed: 20133914, 20038971). Many tumors overexpress wild-type IDH1 to mitigate oxidative stress and meet the high metabolic demands of rapid proliferation, making it a potential therapeutic target (PubMed: 28673550, 32165413). Although most clinical inhibitors are designed to be mutant-selective to avoid disrupting normal cellular metabolism, the development of wild-type or pan-IDH1 inhibitors is being explored for specific metabolic vulnerabilities in various malignancies (PubMed: 25517748, 27323441).

Other names

Isocitrate dehydrogenase 1 (NADP+), solubleIDPIDPCPICDNADP(+)-specific isocitrate dehydrogenase, cytosolicOxalosuccinate decarboxylaseCytosolic NADP-isocitrate dehydrogenase

Inhibition of the enzymatic conversion of isocitrate to alpha-ketoglutarate and the concomitant reduction of NADP+ to NADPH (PubMed: 23412276, 25517748).