Copper-zinc superoxide dismutase activity

Pasinelli, P., Borchelt, D. R., Houseweart, M. K., Cleveland, D. W. and Brown, R. H. Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. Neurobiology 95 15763-15768,1998. 

Transition metal hydroperoxo species are well established as important intermediates in the oxidation of hydrocarbons (8,70,71). As they relate to the active oxygenating reagent in cytochrome P-450 monooxygenase, (porphyrin)M-OOR complexes have come under recent scmtiny because of their importance in the process of (poiphyrin)M=0 formation via 0-0 cleavage processes (72-74). In copper biochemistry, a hydroperoxo copper species has been hypothesized as an important intermediate in the catalytic reaction of the copper monooxygenase, dopamine P-hydroxylase (75,76). A Cu-OOH moiety has also been proposed to be involved in the disproportionation of superoxide mediated by the copper-zinc superoxide dismutase (77-78). Thus, model Cun-OOR complexes may be of... 

Guanine is the most easily oxidizable natural nucleic acid base [8] and many oxidants can selectively oxidize guanine in DNA [95]. Here, we focus on the site-selective oxidation of guanine by the carbonate radical anion, COs , one of the important emerging free radicals in biological systems [96]. The mechanism of COs generation in vivo can involve one-electron oxidation of HCOs at the active site of copper-zinc superoxide dismutase [97, 98], and homolysis of the nitrosoperoxycarbonate anion (0N00C02 ) formed by the reaction of peroxynitrite with carbon dioxide [99-102]. 

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. 

Fig. 6.2. Schematic structure of the active site of copper-zinc superoxide dismutase [72]. The zinc ion can be substituted, among others, by copper(II), cobalt(II) and nickel(II) ions.

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. ... 

The redox-active copper of copper/zinc-superoxide dismutases [24,37] is associated with an E° for [Cun/Cur] of +0.3-0.4 V, approximately mid-way between the redox potential E° aq for O2 reduction to 02 relative to 1M 02, and that for 02 reduction to H2O2, enabling dismutation to take place. 

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. 

C2. Ceballos-Picot, I., Trivier, J.-M., Nicole, A., Sinet, P.-M., and Thevenin, M., Age-correlated modifications of copper-zinc superoxide dismutase and glutathione-related enzyme activities in human erythrocytes. Clin. Chem. 38 66-70 (1992). 

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. 

Yoo, H.Y., M.S. Chang and H.M. Rho. The activation of the rat copper/zinc superoxide dismutase gene by hydrogen peroxide through the hydrogen peroxide-responsive element and by paraquat and heat shock through the same heat shock element. J. Biol. Chem. 21 A 23887—23892, 1999. 

Gralla EB, Thiele DJ, Silar P, Valentine JS. ACE1, a copper-dependent transcription factor, activates expression of the yeast copper, zinc superoxide dismutase gene. Proc Natl Acad Sci USA 88 8558-8562, 1991. 

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