Superoxide peroxynitrite anion production

The protonated form of peroxynitrite anion, peroxynitrous acid, is highly reactive with biologic molecnles. Hence, the production of nitric oxide from nitric oxide synthase (a complex enzyme containing several cofactors, and a heme group that is part of the catalytic site), which catalyzes the formation of NO from oxygen and arginine, can render ceUnlar components such as DNA susceptible to superoxide-mediated damage (1). 

XOR is a cytoplasmic enzyme and a ready source of electrons for transfer to molecular oxygen to form reactive oxygen species such as superoxide and peroxide. It is therefore thought to be involved in free radical-generated tissue injury and has been implicated in the pathogenesis of ischemia-reperfusion damage. Moreover, it has recently been implicated in the production of peroxynitrite (89), and carbonate radical anion (92), both potent biological oxidants. Its exact role in lipid peroxidation, inflammation, and infection needs... 

The production of superoxide anions is one of the major factors involved in NO toxicity because superoxide anions can react with NO to form the highly toxic free-radical peroxynitrite. A pivotal role for superoxide anions in NO-related insults is emphasized by results showing that transgenic mice overexpressing superoxide dismutase (SOD) are resistant to brain ischemia. Superoxide can protect against SNP-induced toxicity. Thus, the superoxide-scavenging properties of EGb 761 are likely to explain, at least in part, its ability to block cell death and the increase in reactive oxygen species accumulation induced by the two NO donors used here, SNP and SIN-1. 

Fig. 3 Formation of peroxynitrite from nitric oxide and superoxide anion and reaction products with carbon dioxide...

NOS products of neurons, epithelial cells and other cells in the lung have both bronchodilator and inflammatory properties (Gaston etal., 1994b) the specific nature of this bioactivity depends on the chemical characteristics of the functional products in the specific microenvironment under consideration. For example, NO is capable of complexing with and affecting the activity of a variety of metalloproteins and enzymes, such as guanylyl cyclase and ribonucleotide reductase (Nathan, 1992 Stamler et al., 1992). NO can also complex with superoxide anion to form peroxynitrite, which has a cytotoxic immune effector role (Radi etal., 1991 Stamler etal., 1992). Furthermore, NO can form iron nitrosyl complexes, which are the putative intracellular macrophage products of iNOS responsible for lysis of intracellular parasites (Hibbs... 

However, these indirect effects of nitric oxide derived products are far more prevalent under pathological conditions such as inflammation, where the production of both NO and by the professional phagocytic cell NADPH oxidase enzyme, and induction of iNOS yields the potent cytotoxic species peroxynitrite. Whilst nitric oxide will react with metal centres (as discussed above) at a rate of 5x 10 M" s and the superoxide anion can be dismutated by SOD at a rate of 2.3x10 M s the combined reaction below (Eq. 9), proceeds at a rate faster than either of these individual reactions ... 

The sites of production of peroxynitrite are more likely to lie in closer proximity to the site of superoxide production as the latter is limited to transfer across the plasma membrane via anion channels, and has a shorter half-life (see above) [18]. It decomposes spontaneously at physiological pH, a process facilitated by the presence of Fe-EDTA and SOD, to yield nitrate (-65%) and nitrogen dioxide and the hydroxyl radical (-35%). Peroxynitrite is not a radical per se, and is less reactive than its protonated form. The pKa of the protonation reaction is 6.8, hence this proceeds efficiently at physiological pH yielding the potent oxidising species, peroxynitrous acid, which correspondingly decomposes to form the hydroxyl radical and nitrogen dioxide shown in Eq. 10 [27] ... 

Fig. 6.17 Reactions of NO in biological systems. NO reacts in biological systems primarily with 02, with the superoxide anion 02 and with transition metals (Me). The products of the reaction, -NOx, metal-NO adducts (Me-NO) and peroxynitrite (OONO ) react further by nitro-sylation of nucleophilic centers. In the cell, these are especially -SH (or thiolate-S ) groups of peptides and proteins (RS).

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