Copper-zinc superoxide dismutase SOD

Y. Tian, M. Shioda, S. Kasahara, T. Okajima, F. Mao, T. Hisabori, and T. Ohsaka, A facilitated electron transfer of copper-zinc superoxide dismutase (SOD) based on a cysteine-bridged SOD electrode. Biochim. Biophys. Acta. 1569, 151-158 (2002). 

Forms of oxygen-derived species produced by activated phagocytes can cause considerable tissue damage unless limited by copper-zinc superoxide dismutase (SOD) which destroys superoxide, 02, or catalase which destroys H202. However, at least two, if not three, other reactive forms of oxygen need to be considered70,71. ... 

Fig. 1. Schematic overview of copper trafficking and homeostasis inside the yeast cell. The actions of Mad and Ace 1, copper-dependent metalloregulatory transcription factors, control the production of copper import [copper transporter (Ctr) and reductase (Fre)] and detoxification/sequestration [metallothionein (MT)] machineries, respectively. Three chaperone-mediated delivery pathways are shown. Atxl shuttles Cu(I) to the secretory pathway P-type ATPase Ccc2 (right). CCS delivers Cu(I) to the cytoplasmic enzyme copper-zinc superoxide dismutase (SOD) (left). Coxl7 shuttles Cu(I) to cytochrome c oxidase (CCO) in the mitochondria (bottom). Mitochondrial proteins Scol and Sco2 may also play a role in copper delivery to the CuA and CuB sites of CCO. Copper metabolism and iron metabolism are linked through the actions of Fet3, a copper-containing ferroxidase required to bring iron into the cell (lower right) (see text).

CD spectroscopy has also provided valuable insight into the chemical stability and chemical denaturation of proteins. A recent study by Rumfeldt etal. examines the guanidinium-chloride induced denaturation of mutant copper-zinc superoxide dismutases (SODs). These mutant forms of the Cu, Zn-SOD enzyme are associated with toxic protein aggregation responsible for the pathology of amyotrophic lateral sclerosis. In this study, CD spectroscopy was used in conjunction with tryptophan fluorescence, enzyme activity, and sedimentation experiments to study the mechanism by which the mutated enzyme undergoes chemical denaturation. The authors found that the mutations in the enzyme structure increased the susceptibihty of the enzyme to form partially unfolded destabilized monomers, rather than the stable metaUated monomer intermediate or native metallated dimer. 

The second protein, copper/zinc superoxide dismutase (SOD, EC 1.15.1.1), catalyzes the disproportionation of O2 (Equation (10)) at a heterodimetallic Cu/Zn active sited 489... 

Diethyldithiocarbamate has long been used as an inhibitor of copper—zinc superoxide dismutase (SOD) (1780,1781). The SOD-Uke activity of bis(dithio-carbamate) complexes derived from amino acids has been determined, with glutamine dithiocarbamate showing high activity (131). Warshawsky et al. (1676) also prepared and assessed a range of dithiocarbamates with ohgoether chains (Fig. 238), which leads to >1000-fold increase in hydrophobicity versus diethyldithiocarbamate, with only a 2.3-fold decrease in SOD-like activity. 

Manganese can also be a catalyst. Manganese [as Mn(III)] in superoxide dismutase from Thermus thermophilus (Stallings et al., 1984, 1985) is surrounded by three histidines, one aspartate oxygen, and water in a trigonal bipyramidal arrangement. The fifth coordination site is occupied by a water molecule. In copper, zinc-superoxide dismutase (Cu,Zn = SOD), as described later, there are two metals (copper and zinc). Each bonds to and are separated by this same histidine group. 

Finally, Zn also plays an important role in Cu,Zn-SOD (copper-zinc superoxide dismutase) for which the structure is shown in Figure 8 ". Although it is well-known that Zn(II) is not involved in electron-transfer chemistry, it is generally believed that the essential role of Zn(II) ion in SODs is to accelerate both the oxidation and reduction of superoxide by controlhng the redox potential of the Cu(II) ion and superoxide ion in the catalytic cycle. ... 

Although zinc itself is not redox-active, some class I enzymes containing zinc in their active sites are known. The most prominent are probably alcohol dehydrogenase and copper-zinc superoxide dismutase (Cu,Zn-SOD). AU have in common that the redox-active agent is another transition-metal ion (copper in Cu,Zn-SOD) or a cofactor such as nicotinamide adenine dinucleotide (NAD+/NADH). The Zn(II) ion affects the redox reaction only in an indirect manner, but is nevCTtheless essential and cannot be regarded simply as a structural factor. 

The enzyme copper, zinc superoxide dismutase (Cu,Zn-SOD, EC 1.15.1.1) catalyzes the disproportionation of superoxide anion to dioxygen and hydrogen peroxide (equations 1 and 2). Crystallographic data can be found in References 41-46. This antioxidant enzyme is present in the cytosol and mitochondrial intermembrane space of eukaryotic cells and in the periplasmic space of bacterial cells as a homodimer of 32 kDa. Each monomer binds one copper and one zinc ion. The reaction mechanism involves the... 

Starting at the far left, we see a water molecule, two common amino acids, alanine and tryptophan, a segment of a DNA double helix, a segment of a protein single helix, and the folded polypeptide chain of the enzyme copper, zinc superoxide dismutase or SOD. 

Copper, silver and gold - The paramagnetism of Cu11 has limited the use of NMR for the direct study of copper complexes, but information is readily obtained from studies of ligand nuclei. For example, the broadening of the NMR signal by copper in copper-zinc and copper-cobalt superoxide dismutases (SODs) has been used to determine the distance between the copper and the proton on bound formate (Sette et al., 1992). Also, broadening of the formate 13C NMR resonance reveals information about the orientation of the formate. 

A particular feature however of a large number of tumour cell types is low levels of manganese-superoxide dismutase (Mn-SOD) activity [138]. Tumours are also usually low in copper, zinc-superoxide dismutase (Cu, Zn-SOD) activity and often also low in catalase activity [138]. Glutathione peroxidase levels are however quite variable. 

From One Type 2 Copper Protein to Another Type 2 Copper Protein. It has been shown that a type 2 copper protein called copper-zinc superoxide dismutase (CuZnSOD) (Figure 15b) shares the same overall scaffold as its copper chaperone protein called copper chaperone for SOD (CCS). All of e zinc site ligands and three of four copper site histidine ligands in CuZnSOD are conserved in human CCS (hCCS). The zinc site in hCCS displayed the same structure as in CuZnSOD. The fourth ligand in the copper site of CuZnSOD is replaced by an aspartate residue in hCCS. Although aspartate could... 

Copper-zinc superoxide dismutase (CuZn-SOD) inhibits cell-mediated oxidation of LDL, but transgenic mice overexpressing CuZn-SOD might have increased atherosclerotic lesion area (388). The role of copper in atherosclerosis is difficult to predict and the studies are conflicting copper is an intrinsic constituent of SOD and ceruloplasmin and a component of Lysyl oxidase (the enzyme involved in collagen synthesis, a major component of ECM). Also, copper ions catalyze oxidative modification of LDL in vitro and possibly in vivo (reviewed in ref. 389). 

IV. Superoxide dismutase (EC 1.15.1.1) Within a cell the superoxide dismutases (SODs) constitute the first line of defense against ROS. Superoxide radical (02) is produced where an electron transport chain is present, as in mitochondria and chloroplasts, but 02 activation may occur in other subcellular locations such as glyoxysomes, peroxisomes, apoplast and the cytosol. Thus SODs are present in all these cellular locations, converting superoxide into hydrogen peroxide and water (i.e. copper/zinc SODs are typically found in the nuclei and cytosol of eukaryotic cells). 

Superoxide dismutase enzymes are functional dimers of molecular weight (Mr) of approximately 32 kDa. The enzymes contain one copper ion and one zinc ion per subunit. Superoxide dismutase (SOD) metalloenzymes function to disproportionate the biologically harmful superoxide ion-radical according to the following reaction ... 

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