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

Isocitrate dehydrogenase 1 (IDH1) is a critical 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 (UniProt O75874). While the wild-type enzyme maintains cellular redox balance and supports lipid synthesis, specific somatic mutations—most frequently at the R132 residue—grant the enzyme a neomorphic gain-of-function (Nature, 2009, 462:739-744). This mutant form converts α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG), which competitively inhibits α-KG-dependent dioxygenases, including histone demethylases and TET family DNA hydroxylases (PubMed, 23412291). The resulting epigenetic hypermethylation leads to impaired cellular differentiation and promotes the development of various malignancies such as acute myeloid leukemia, low-grade gliomas, and cholangiocarcinoma (FDA, Tibsovo Prescribing Information). Pharmacological targeting of mutant IDH1 with small-molecule inhibitors aims to lower 2-HG levels, thereby restoring normal epigenetic signaling and inducing the differentiation of malignant cells (StatPearls, NBK545234). These inhibitors are specifically designed to bind the mutant protein, though some dual inhibitors also target the related IDH2 isoform or show varying degrees of selectivity against the wild-type enzyme (Nature Reviews Cancer, 2017, 17:71-83). Clinical management of patients on these therapies requires monitoring for differentiation syndrome, a potentially fatal condition characterized by rapid proliferation and differentiation of myeloid cells (FDA, Rezlidhia Label).

Other names

Isocitrate dehydrogenase 1IDPIDPCPICDNADP(+)-specific isocitrate dehydrogenase, cytosolicOxalosuccinate decarboxylase

Small-molecule inhibition of the mutant IDH1 enzyme to suppress the production of the oncometabolite D-2-hydroxyglutarate (2-HG), thereby reversing epigenetic dysregulation and promoting cellular differentiation.