Isocitrate Dehydrogenase (IDH)

Isocitrate dehydrogenase (IDH), one of the key enzymes in the citric acid cycle, catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) generating carbon dioxide and NADPH/NADH. IDHs belong to a large ancient family of enzymes that play central roles in energy metabolism, amino acid biosynthesis and vitamin production.

IDH protein family consists of three self-regulating enzymes (IDH1, IDH2, and IDH3). IDH1 and IDH2 are both nicotinamide adenine dinucleotide phosphate (NADP)-dependent enzymes that catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), while producing NADPH either in peroxisomes and the cytosol (IDH1) or in mitochondria (IDH2). IDH3 catalyzes the same reaction in the mitochondria, but in a NAD-dependent fashion. Mutations in IDH1 and IDH2 have been demonstrated in a variety of malignancies. IDH inhibitors have engendered hope in IDH1/2 mutant myeloid malignancies.