isocitratdehydrogenase

Isocitrate dehydrogenase, often abbreviated as IDH, refers to a family of enzymes that catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (2-oxoglutarate) in cellular metabolism. In the reaction, NAD+ or NADP+ is reduced to NADH or NADPH, and carbon dioxide is released. Different IDH isoforms are localized in distinct cellular compartments and use different cofactors, linking the citric acid cycle to biosynthetic needs and redox balance.

In humans there are three major isozymes: IDH3, which is mitochondrial and NAD+-dependent and functions in the classic citric acid cycle; and the NADP+-dependent IDH1 (cytosolic) and IDH2 (mitochondrial). IDH3 provides NADH for oxidative phosphorylation, while IDH1 and IDH2 generate NADPH, a reducing equivalent used in fatty acid synthesis, nucleotide synthesis, and defense against oxidative stress.

Biological role and metabolic significance: By converting isocitrate to alpha-ketoglutarate, IDH links carbohydrate metabolism to the production of key metabolic precursors. The NADPH produced by IDH1 and IDH2 supports reductive biosynthesis and antioxidant systems, contributing to cellular redox homeostasis and biosynthetic capacity. The activity of IDH enzymes influences flux through the citric acid cycle and related pathways such as glutamate and glutamine metabolism.

Clinical relevance: Mutations in IDH1 or IDH2 are found in several cancers, notably gliomas and acute myeloid leukemia. These mutations confer a neomorphic activity that produces the oncometabolite 2-hydroxyglutarate, which can alter epigenetic regulation and differentiation. Therapeutic inhibitors targeting mutant IDH1 or IDH2 (for example, IDH1 and IDH2 inhibitors) have been approved for certain cancers and are the subject of ongoing research.