Superoxide dismutases Cu,Zn-SOD

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. 

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... 

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. 

Cu,Zn-Superoxide Dismutase. Although Cu,Zn-superoxide dismutase (Cu,Zn-SOD) only occurs in eukaryotes, it may be found in almost all types of eu-... 

Since the copper-dependent and zinc modulated superoxide dismutase (Cu-Zn SOD) is normally found in cytosol of cells of all aerobic organisms... 

The production of superoxide from secondary reactions of radiation-produced radicals can contribute to the oxygen enhancement of radiation damage, because superoxide can further react to give reactive oxidizing agents. The enzyme superoxide dismutase (Cu/Zn SOD) catalyzes the disproportionation of superoxide [97] ... 

The radical anion superoxide 02 is a product of activated leukocytes and endothelial cells and has been postulated to be a mediator of isch-emia-reperfusion injury and inflammatory and vascular diseases. Various superoxide dismutase (SOD) enzymes are known Cu,Zn-SOD in the cytoplasm of eukaryotic cells, Mn-SOD in mitochondria, and Fe-SOD and Mn-SOD in prokaryotic cells. They catalyze the conversion of 02 into H202 and 02... 

Mn superoxide dismutases are found in both eubacteria and archaebacteria as well as in eukaryotes, where they are frequently found in mitochondria. They (Figure 16.1) have considerable structural homology to Fe SODs both are monomers of 200 amino acid and occur as dimers or tetramers, and their catalytic sites are also very similar. They both catalyse the two-step dismutation of superoxide anion and, like the Cu-Zn SODs, avoid the difficulty of overcoming electrostatic repulsion between two negatively charged superoxide anions by reacting with only one molecule at a time. As in the case of Cu-Zn SOD, a first molecule of superoxide reduces the oxidized (Mn3+) form of the enzyme, releasing... 

Although the details of the structure of superoxide dismutase (SOD), one form of which is a Cu,Zn-enzyme (Cu,Zn-SOD), have been well described previously (Getzoff etal., 1983), a brief description is repeated here, for the geometry of the copper site as well as the topology of its fold is relevant to all copper enzymes. 

XAS has proved particularly successful in deilning the structural changes which occur upon reduction and anion binding to superoxide dismutase thus providing a unique insight into the structure-function relationships in the Cu Zn SOD. The anion-binding studies have been particularly relevant due to the close similarity of the anions such as cyanide and azide to the superoxide substrate. 

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. ... 

In conclusion no other Cu protein has a superoxide dismutase activity comparable to that of (Cu,Zn)-SOD. 

Fig. 7. A Structural representation of Cu-Zn superoxide dismutase (SOD) active site (from Ref. 31c). B X-band (left) (77K v = 9.2 GHz) (from Ref. 25) and Q-band (right) (173 K v = 35 GHz) (from Ref. 26) EPR spectra of bovine Cu-Zn SOD. C Optical absorption spectra of native...

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. 

Superaxide Dismutase (SOD). Manganese-dependent SOD is a mitochondrial enzyme and is an important factor in limiting oxygen toxicity it is one of the most studied enzymes in human biochemistry. The enzyme catalyzes the breakdown of the superoxide radical OJ to H2O2, which is then removed by catalase and glutathione peroxidase. The half-life of this enzyme in blood serum is longer than that of the cytoplasmic Cu, Zn SOD. 

The main part of mitochondrial Oy is vectorially released to the matrix, where it encounters specific intramitochondrial Mn-superoxide dismutase (Mn-SOD) [21-23] (reaction 4 ). Steady state concentrations of 0.2-0.3 nM were estimated for the mitochondrial matrix, with a content of 10-40 pM Mn-SOD reaction centers [24]. The Oy released into the intermembrane space [11] reacts with cytochrome c, located on the P side of the inner membrane, and with the Cu, Zn-SOD of the intermembrane space [25] ... 

Okado-Matsumoto A, Fridovich I (2001) Subcellular distribution of superoxide dismutases (SOD) in rat liver Cu,Zn-SOD in mitochondria. J Biol Chem 276 38388-38393... 

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