Normal Functions of NADP1-Dependent

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxyl-ation of isocitrate to a-ketoglutarate and reduce NAD(P)1 to NAD(P)H. This process involves oxidation of isocitrate to oxalosuc-cinate, with NAD(P)H as the electron acceptor, followed by decar-boxylation of oxalosuccinate to form a-ketoglutarate. Humans and other eukaryotes have both NAD1- and NADP1-dependent IDHs. NAD1-dependent IDH, or IDH3, is a multisubunit enzyme that is localized to the mitochondrial matrix and is classically thought to play a central role in aerobic energy production in the tricarboxylic acid (TCA) cycle. IDH1 and IDH2 are NADP1 dependent, share considerable sequence similarity (70 % identity in humans), and are unrelated to IDH3. Importantly, IDH1 and IDH2 catalyze revers-ible reactions and have no known allosteric modifiers, whereas the reaction catalyzed by IDH3 is irreversible and allosterically regu-lated by a variety of positive (calcium, ADP, and citrate) and nega