IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial)6

Abstract

Human Isocitrate dehydrogenase (IDH) occurs in three isozymes, IDH1, located in the cytoplasm, and IDH2 and IDH3 located in the mitochondria. IDH functions as part of the tricarboxylic acid (TCA) cycle and catalyzes the reversible conversion of isocitrate to alpha ketoglutarate (α-KG)/2-oxoglutarate (2-OG), thus promoting the activity of dioxygenases that require α-KG as a cosubstrate. IDH1 and IDH2 use NADP+ as a cofactor, producing NADPH in the process (NADPH plays a vital role in the regeneration of the antioxidant glutathione), whereas IDH3 uses NAD+ as a cofactor and produces NADH. Somatic heterozygous mutations in the active site of IDH1 (at position R132) or IDH2 (at position R140 or R172) have been reported in a spectrum of human tumors: gliomas, hematologic malignancies including myeloproliferative neoplasms, myelodysplastic syndromes and acute myeloid leukemia, and also angioimmunoblastic T-cell lymphoma and primary central nervous system lymphoma, cholangiocarcinoma, chondrosarcomas, and other malignancies. IDH mutations lead to a neomorphic enzymatic activity of the mutated IDH enzyme, resulting in the conversion of α-KG to R-2-hydroxyglutarate (R2-HG). Supra-normal levels of intracellular 2-HG interfere with several α-KG- dependent dioxygenases, notably enzymes involved in methylation of histones (histone lysine demethylases, KDMs) and DNA (TET family of DNA hydroxylases).