IDH1

IDH1 stands for isocitrate dehydrogenase 1, a cytosolic enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) while reducing NADP+ to NADPH. As a cytosolic homodimer that binds zinc, IDH1 supports cellular redox balance and biosynthetic processes, supplying NADPH for fatty acid synthesis and the detoxification of reactive oxygen species.

In normal metabolism, IDH1 participates in cytosolic citrate and isocitrate metabolism and contributes to maintaining cellular redox and lipid-building capacity. It is one of several isocitrate dehydrogenase enzymes, with IDH2 in mitochondria and IDH3 also in mitochondria performing related reactions with different cofactors.

Mutations in IDH1 occur in a subset of cancers, most notably in lower-grade gliomas and secondary glioblastomas, as well as in a minority of other tumors. The most common alteration is the R132H substitution, though other amino acid changes are observed. Mutant IDH1 proteins reduce α-KG to 2-hydroxyglutarate (2-HG) using NADPH, gaining a neomorphic activity that leads to its accumulation.

2-Hydroxyglutarate acts as an oncometabolite by inhibiting α-KG–dependent dioxygenases, including TET family DNA demethylases and JmjC-domain–containing histone demethylases. This results in widespread epigenetic changes, altered gene expression, and impaired cellular differentiation, contributing to tumor development and progression.

Clinical relevance and therapy: IDH1 mutations serve as diagnostic and prognostic markers in gliomas and other cancers. Drugs targeting mutant IDH1, such as small-molecule inhibitors, have been developed and approved for certain IDH1-mutant cancers, with ongoing trials in additional tumor types.