title: Activation of superoxide dismutases: putting the metal to the pedal.
abstract: Superoxide dismutases (SOD) are important anti-oxidant enzymes that guard against superoxide toxicity. Various SOD enzymes have been characterized that employ either a copper, manganese, iron or nickel co-factor to carry out the disproportionation of superoxide. This review focuses on the copper and manganese forms, with particular emphasis on how the metal is inserted in vivo into the active site of SOD. Copper and manganese SODs diverge greatly in sequence and also in the metal insertion process. The intracellular copper SODs of eukaryotes (SOD1) can obtain copper post-translationally, by way of interactions with the CCS copper chaperone. CCS also oxidizes an intrasubunit disulfide in SOD1. Adventitious oxidation of the disulfide can lead to gross misfolding of immature forms of SOD1, particularly with SOD1 mutants linked to amyotrophic lateral sclerosis. In the case of mitochondrial MnSOD of eukaryotes (SOD2), metal insertion cannot occur post-translationally, but requires new synthesis and mitochondrial import of the SOD2 polypeptide. SOD2 can also bind iron in vivo, but is inactive with iron. Such metal ion mis-incorporation with SOD2 can become prevalent upon disruption of mitochondrial metal homeostasis. Accurate and regulated metallation of copper and manganese SOD molecules is vital to cell survival in an oxygenated environment.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. vculotta@jhsph.edu
authors.forename: Valeria Cizewski
authors.initials: VC
authors.lastname: Culotta
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.forename: Thomas V
authors.initials: TV
authors.lastname: O'Halloran
mesh_terms: D004789:Enzyme Activation; D007501:Iron / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation; D013347:Subcellular Fractions / Q000201:enzymology; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D007501:Iron; D013482:Superoxide Dismutase