Superoxide dismutases Mn-SOD

TNF-a elicits a wide range of responses in cells and tissues. Apart from causing the lysis of certain tumours (by mechanisms probably related to the ability of the target to induce the synthesis of the mitochondrial manganese-dependent superoxide dismutase, Mn-SOD), it can also kill normal cells. These effects on normal cells are more apparent when biosynthesis is blocked - for example, by the addition of inhibitors of macromolecular bio-... 

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. 

In ALS, abundant evidence points to the effects of per-oxynitrite in affected tissues. Significant increases in levels of NT moieties are detected on CSF proteins from ALS patients (Aoyama et al., 2000 Shaw and Williams, 2000), including Mn superoxide dismutase (Mn-SOD) which is only slightly increased in patients with AD and PD (Chou et al., 1996 Aoyama et al., 2000). Moreover, NT immunoreactivity is associated with motor neurons of the spinal cord and axons (Calin-gasan et al., 2005), and co-localizes to axonal conglomerates and spheroid neurofilament accumulations of upper and lower motor neurons (Chou et al., 1996) and with Ap-40 depositions within abnormal neurons (Calingasan et al., 2005). 

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] ... 

Inagaki, S., Suzuki, K., Taniguchi, N., and Takagi, H. (1991). Localization of Mn-superoxide dismutase (Mn-SOD) in cholinergic and somatostatin-containing neurons in the rat neostriatum. Brain Res. 549, 174-177. 

Biochemically, manganese is considered an essential trace element, participating in a number of hiomolecules superoxide dismutase (Mn-SOD), catalase, Mn-ribonucleotide reductase, Mn-peroxidase, ligninase, the o>ygen-evolving centre (OEC) of photosystem ii (PS-ii), and Mn-thiosulfate oxidase. The enzymes mechanisms are very diverse and include oxo-atom transfer (four-electron oxidation of water to diojygen in PS-ii, extradiol dioxygenase), electron transfer (SOD, catalase), reduction of ribonucleotides to water and deoxyribonucleotides and oxidation of thiosulfate to sulfate. ... 

Little information is available in the scientific literature on the contribution of ROls in regulating the type II cell response to direct interactions with silica particles. Increases in manganese superoxide dismutase (Mn-SOD) protein can be localized to type II cells following in vivo silica exposure in rats (143). Type II cells respond to an oxidant stress, such as hyperoxia, by increasing antioxidant enzymes (144) and chemokines (145,146). Thus, it is reasonable to hypothesize that the type II cell response to silica involves an oxidant-mediated component. 

Superoxide dismutase (SOD) enzymes are metallopro-teins that detoxify superoxide anions (02) by converting them to H202, which is subsequently reduced to water. SOD enzymes include the manganese (Mn) enzyme in mitochondria (SOD2) and the Cu/Zn... 

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... 

Manganese is the cofactor for catalases, peroxidases and superoxide dismutases, which are all involved in the detoxification of reactive oxygen species (SOD). We consider here the widely distributed Mn SOD, and then briefly describe the dinuclear Mn catalases. 

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... 

In contrast, antioxidant enzymes can efficiently counteract all UV-induced ROS (Aguilera et al. 2002). These enzymes are represented by superoxide dismutase (SOD), catalase and glutathione peroxidase as well as those involved in the ascorbate-glutathione cycle, such as ascorbate peroxidase, mono-dehydroascorbate reductase, dehydroascorbate reductase and glutathione reductase. One of the most important classes of antioxidant enzymes is the SOD family, which eliminate noxious superoxide radical anions. Different metalloforms of SOD exist (Fe, Mn, CuZn and Ni), which due to their intracellular localisation protect different cellular proteins (Lesser and Stochaj 1990). 

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. 

Fe- and Mn-containing superoxide dismutases have, moreover, been isolated. They show striking sequence homologies. (Fe)-SOD has mainly been found in prokaryotes. (Mn)-SOD occurs in prokaryotes, (20,000), in the matrix of mitochondria, although encoded by the nucleus, and also in the cytosol of e.g. liver cells (human, chicken in contrast with rat)... 

Surprisingly, too, there are claims of higher oxidation states of Mn in some systems, e.g. Mnlv in photosynthetic(II) chloroplast systems and Mn111 in acid phosphatase. In the latter enzyme Tyr and Cys residues appear to form part of the metal-binding site. The metal is also involved in the phosphate binding. While superoxide dismutase (SOD) is more generally found with Cu and Zn as the active metals, an Mn-SOD form is found in certain bacteria. The Mn oscillates between different oxidation states in its catalytic activity.149... 

Superoxide dismutase (SOD) mimic, synthesized from ferrioxamine B and Mn4+, which catalyzes 02 is of special interest. Hence, the activity of this compound equals about 0.1% of SOD activity (calculated per Mn content) [69],... 

Two different superoxide dismutases (SODs) are found in mammalian tissues a Cu/Zn-containing enzyme which is found in the cytoplasm of most cells, and a further Mn-containing enzyme present within the mitochondrial compartment [1], Both enzymes catalyse the same reaction ... 

The general acceptance of free radicals in biological systems did not occur until the discovery (Mila) of superoxide dismutase (SOD), of which there are two enzymes, cytoplasmic CuZn-SOD and mitochondrial Mn-SOD. These enzymes catalyze the following reaction ... 

While the stoichiometries of the Mn SOD enzymes appear to vary, the properties of the Mn-binding site do not. This is borne out in the electronic spectra of these proteins, which display a great degree of similarity despite the diversity of sources from which they have been isolated (Table II). This type of spectrum is distinctive for manganese in the trivalent oxidation state (3). The native enzymes are EPR silent, as might be anticipated if they contained Mn solely as the trivalent ion (S = 2) (1, 6,12,18-20, 24). However, when the enzymes are denatured, the characteristic six-line pattern of Mn(II) (I = 5/2) appears. Magnetic susceptibility studies with the E. coli SOD were consistent with the presence of a monomeric Mn(III) complex with a zero-field splitting of 1 to 2 cm-1 (4). The enzymes are additionally metal specific (however, see Refs. 36 and 37) metal reconstitution studies with E. coli and B. stearothermophilus revealed a strict requirement for Mn for superoxide dismutase activity (2, 22, 23). 

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