Superoxide dismutation , mechanism

The superoxide dismutation mechanism (Figure 3) [5] is consistent with the preceding structural data. 

Figure 3 Superoxide dismutation mechanism under physiological conditions. (After Ref. 5.)...

Besides the superoxide dismutation mechanism, the reactivity of metal centers, in particular manganese complexes, toward NO is very much dependent on the possibility for binding a substrate molecule. As it will be shown later, the possibility that MnSOD enzymes and some mimetics can react with NO has been wrongly excluded in the literature, simply based on the known redox potential for the (substrate) free enzymes, mimetics, and NO, respectively. Therefore, the general fact that, upon coordination, redox potentials of both the metal center and a coordinated species are changed should be considered in the case of any inner-sphere electron-transfer process as a possible reaction mechanism. 

Thus, the mechanism of MT antioxidant activity might be connected with the possible antioxidant effect of zinc. Zinc is a nontransition metal and therefore, its participation in redox processes is not really expected. The simplest mechanism of zinc antioxidant activity is the competition with transition metal ions capable of initiating free radical-mediated processes. For example, it has recently been shown [342] that zinc inhibited copper- and iron-initiated liposomal peroxidation but had no effect on peroxidative processes initiated by free radicals and peroxynitrite. These findings contradict the earlier results obtained by Coassin et al. [343] who found no inhibitory effects of zinc on microsomal lipid peroxidation in contrast to the inhibitory effects of manganese and cobalt. Yeomans et al. [344] showed that the zinc-histidine complex is able to inhibit copper-induced LDL oxidation, but the antioxidant effect of this complex obviously depended on histidine and not zinc because zinc sulfate was ineffective. We proposed another mode of possible antioxidant effect of zinc [345], It has been found that Zn and Mg aspartates inhibited oxygen radical production by xanthine oxidase, NADPH oxidase, and human blood leukocytes. The antioxidant effect of these salts supposedly was a consequence of the acceleration of spontaneous superoxide dismutation due to increasing medium acidity. 

The inhibition of lipid peroxidation by metalloporphyrins apparently depends on metal ions because only compounds with transition metals were efficient inhibitors. Therefore, the most probable mechanism of inhibitory effects of metalloporphyrins should be their disuniting activity. Manganese metalloporphyrins seem to be more effective inhibitors than Trolox (/5o = 204 pmol I 1) and rutin (/50 112 pmol I 1), and practically equal to SOD (/50= 15 pmol I 1). The mechanism of inhibitory activity of manganese and zinc metalloporphyrins might be compared with that of copper- and iron-flavonoid complexes [167,168], which exhibited enhanced antiradical properties due to additional superoxide-dismuting activity. 

The mechanisms of superoxide-dismuting activity of SODs are well established. Dismutation of superoxide occurs at copper, manganese, or iron centers of SOD isoenzymes CuZnSOD, MnSOD, or FeSOD. These isoenzymes were isolated from a variety of sources, including humans, animals, microbes, etc. In the case of CuZnSOD, dismutation process consists of two stages the one-electron transfer oxidation of superoxide by cupric form (Reaction (1)) and the one-electron reduction of superoxide by cuprous form (Reaction (2)). 

Similar reactions are catalyzed by Mn and Fe centers of MnSOD and FeSOD. It is obvious that before participation in Reaction (2), superoxide must be protonized to form hydroper-oxyl radical HOO by an outer-sphere or an intra-sphere mechanisms. All stages of dismuting mechanism, including the measurement of elementary rate constants, have been thoroughly studied earlier (see, for example, Ref. [2]). 

The mechanism of catalytic superoxide dismutation by nitroxides can be presented as follows [27] ... 

Bull C, McClune GJ, Fee JA (1983) The mechanism of Fe-EDTA catalyzed superoxide dismutation. J Am Chem Soc 105 5290-5300... 

Scheme 1 A possible mechanism for superoxide dismutation catalyzed by Cu, Zu SOD, emphasizing Cu VCu cycling. (Ref. 13. Reproduced by permission of Nature Publishing Group)...

MnIII/n are much more positive in small molecules than those of FeIII/n [6], the MnSOD must lower the MnIII/n couple to a range suitable for superoxide dismutation while FeSOD raises the Fem/n couple accordingly. Early support for this explanation came from measuring the Em of Fe-substituted MnSOD [Fe(Mn) SOD] in comparison to that of FeSOD. Indeed, the reduction potential of Fe(Mn) SOD drops from the wild-type value of approximately 200 mV to —240 mV (vs. NHE). This report launched extensive study by Miller, Brunold, and others of the mechanisms by which these highly similar proteins tune their active site m [7,8]. 

Fio. 53. Presumed scheme of the superoxide dismutation reaction by Cu2ZnjS0D prior to elucidation of the 2S0D crystal structure. Arg-141 is not involved in the mechanism. 

The superoxide dismutation can be spontaneous or can be catalyzed and therefore significantly accelerated by the enzyme superoxide dismutase (SOD). The superoxide not only generates lydrogen peroxide (H2O2) but also stimulates its conversion into OH radicals, which are actually extremely strong oxidizers very effective in sterilization through a chain oxidation mechanism (to be especially discussed in Section 12.1.5). The H2O2 conversion into OH, known as the Fenton reaction, proceeds as a redox process provided by oxidation of metal ions (for example, Fe +) ... 

In the past years, it has been shown by us and others 5b,15b,27) that the mechanism of superoxide dismutation by small metal complexes proceeds predominantly by an inner-sphere mechanism. 

Fig. 8. Pustulated mechanism for superoxide dismutation by manganese pentaazamacrocyclic complexes (modified from Ref. 7b).

That inner-sphere electron transfer plays an important role within the SOD mechanism is shown by our preliminary experiments with the eight-coordinate Mn(II) complex (Fig. 11). Although the redox potential of this complex is similar to the redox potentials of some proven seven-coordinate Mn(II) SOD mimetics (approximately +0.78V vs. NHS) (13a,g,31), the studied eight-coordinate Mn(II) complex demonstrates no ability for catalytic superoxide dismutation. This can be explained in terms of the saturated coordination geometry around the metal center and shows that, for SOD activity, the complex redox potential is not the only important requirement. In the case of these complexes, with a relatively high redox potential, coordination of superoxide is crucial for its efficient reduction. 

In 1989, we showed [142] that the Fe2+(rutin)2 complex is a more effective inhibitor than rutin of asbestos-induced erythrocyte hemolysis and asbestos-stimulated oxygen radical production by rat peritoneal macrophages. Later on, to evaluate the mechanisms of antioxidant activities of iron rutin and copper-rutin complexes, we compared the effects of these complexes on iron-dependent liposomal and microsomal lipid peroxidation [165], It was found that the iron rutin complex was by two to three times a more efficient inhibitor of liposomal peroxidation than the copper-rutin complex, while the opposite tendency was observed in NADPH-dependent microsomal peroxidation. On the other hand, the copper rutin complex was much more effective than the iron rutin complex in the suppression of microsomal superoxide production, indicating that the copper rutin complex indeed acquired additional SOD-dismuting activity because superoxide is an initiator of NADPH-dependent... 

High values of reaction rates for the two dismutation steps confirm the ability of both nitroxides TPO and 3-CP to be SOD mimics. However, as follows from the above mechanism, hydroperoxyl radical and not superoxide must participate in the first dismutation step (Reaction (5)). (As expected, a rate constant for the reaction of nitroxides with superoxide is very low <103 1 mol 1 s-1 [27].) Therefore, superoxide had to be protonated before participating in Reaction (5), which will diminish the total catalytic process at physiological pH and increase it at lower pH values. 

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