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

Isocitrate dehydrogenase 1 (IDH1) is a critical metabolic enzyme located in the cytoplasm and peroxisomes that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), simultaneously reducing NADP+ to NADPH (UniProt: O75874). This reaction serves as a major source of cytosolic NADPH, which is essential for fatty acid and cholesterol biosynthesis, as well as for maintaining the cellular antioxidant pool via the glutathione and thioredoxin systems (NCBI Gene: 3417). While IDH1 is frequently discussed in the context of its oncogenic mutations (e.g., R132H) that produce the oncometabolite 2-hydroxyglutarate, the wild-type (WT) form is increasingly recognized as a distinct therapeutic target. In several malignancies, such as IDH1-wild-type glioblastoma and certain solid tumors, the enzyme is often overexpressed to support the high metabolic demands and provide protection against oxidative stress (Zarei et al., 2022). Therapeutic strategies targeting wild-type IDH1 involve small-molecule inhibitors, such as pan-IDH inhibitors or WT-selective compounds, which aim to deplete NADPH levels and sensitize tumor cells to chemotherapy or radiation (PubChem CID: 71311). Clinical development in this area focuses on balancing the inhibition of tumor metabolism with the potential for systemic toxicity resulting from the disruption of normal cellular redox homeostasis.

Other names

IDPIDCDIDPCPICDIsocitrate dehydrogenase [NADP] cytoplasmicNADP(+)-specific ICDHOxalosuccinate decarboxylase

Inhibition of the enzymatic conversion of isocitrate to alpha-ketoglutarate, thereby reducing the production of NADPH and disrupting cellular redox homeostasis and biosynthetic pathways in cancer cells.