Reactivity peroxynitrous acid

At physiological pH, ONOO- protonates to peroxynitrous acid (ONOOH) which disappears within a few seconds, the end product being largely nitrate. The chemistry of peroxynitrite/peroxynitrous acid is extremely complex, although addition of ONOO to cells and tissues leads to oxidation and nitration of proteins, DNA and lipids with a reactivity that is comparable to that of hydroxyl radicals. 

It should be noted that Reaction (4) is not a one-stage process.) Both free radical N02 and highly reactive peroxynitrite are the initiators of lipid peroxidation although the elementary stages of initiation by these compounds are not fully understood. (Crow et al. [45] suggested that trans-ONOO is protonated into trans peroxynitrous acid, which is isomerized into the unstable cis form. The latter is easily decomposed to form hydroxyl radical.) Another possible mechanism of prooxidant activity of nitric oxide is the modification of unsaturated fatty acids and lipids through the formation of active nitrated lipid derivatives. 

The second proposal is a bit more imaginative and arises from the above arguments that 0—0 bond homolysis is much too slow to be involved in oxidations by peroxynitrate. Pryor and coworkers invoked the intermediacy of a metastable form of peroxynitrous acid (HO—ONO ) in equilibrium with its ground state. This so-called excited state of peroxynitrous acid has, to date, eluded detection or characterization by the experimental community. However, recent high-level theoretical calculations by Bach and his collaborators have presented plausible evidence for the intermediacy of such a shortlived species with a highly elongated 0—0 bond and have confirmed its involvement in the oxidation of hydrocarbons (see below). The discovery of this novel series of biologically important oxidants has fostered a new area of research in both the experimental and theoretical communities. In this chapter we will describe many of the more pertinent theoretical studies on both the physical properties and chemical reactivity of peroxynitrous acid. 

The similarity of the structure of peroxynitrous acid to the simplest peroxy acid, per-oxyformic acid, immediately raised the question as to its relative reactivity as an oxygen atom donor. This became particularly relevant when it was recognized that the 0—0 bond dissociation energy (AG° = 21 kcalmoR ) of HO—ONO was much lower than that of more typical peroxides. Consequently, peroxynitrous acid (HO-ONO) can be both a one- and two-electron oxidant. Since the 0-0 bond in HO-ONO is so labile, its chemistry is also consistent in many cases with that of the free hydroxyl radical. 

Peroxynitric acid (O2NO—OH) is another important reactive two-electron oxidative species in this series of nitrogen-containing peroxides. The activation barriers reported by Houk and coworkers for two-electron oxidation of NH3, H2S and H2C=CH2 are similar to those found for HO—ONO . It differs from peroxynitrous acid mainly in its... 

While it is well established that HO—ONO can be involved in such two-electron processes as alkene epoxidation and the oxidation of amines, sulfides and phosphines, the controversy remains concerning the mechanism of HO-ONO oxidation of saturated hydrocarbons. Rank and coworkers advanced the hypothesis that the reactive species in hydrocarbon oxidations by peroxynitrous acid, and in lipid peroxidation in the presence of air, is the discrete hydroxyl radical formed in the homolysis of HO—ONO. The HO—ONO oxidation of methane (equation 7) on the restricted surface with the B3LYP and QCISD methods gave about the same activation energy (31 3 kcalmol" ) irrespective of basis set size . ... 

Among the reactive peroxides, peroxynitrous acid, ONOOH and its anion, peroxynitrite [pKa(ONOOH) = 6.5-6.8 (Logager and Sehested 1993 Goldstein and Czapski 1995 Kissner et al. 1997)] play an important role in cellular systems, and their reactions must be discussed here in some detail. 

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). 

Peroxynitrous acid, however, is not stable and decomposes to yield HO and NO2 [224]. When NO2 reacts with NO, N2O3 is generated. A comprehensive discussion of these RNS is outside the scope of this paper. However, it should be noted that all these RNS are highly reactive, short-lived species. Therefore, their quantitative assay is a challenging task particularly under in vivo conditions Nitrite (NO2 ) that results e.g. from the decomposition of N2O3, is often used as a marker of the NO production under in vivo conditions and it is known that under inflammatory conditions the concentration of nitrite is strongly elevated. For instance it was shown that nitrite concentrations of up to 4 mmol/1 can be detected in synovial fluids of the patients suffering from RA [226]. 

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. 3. Production of reactive species. (A) ROS can be produced from the weak radical oxygen in the mitochondria and endoplasmic reticulum, by various enzymatic reactions, and from oxyhemoglobin. Normally, nontoxic hydrogen peroxide can give rise to the powerful hydroxyl radical in the presence of transition metals (R5). Oxygen can also be induced to react with biomolecules by transition metals and enzymes. RNS can be produced by reaction of superoxide anion radical with the weak radical nitric oxide. These can react to form the powerful oxidant peroxynitrite/peroxynitrous acid, which can cause formation of other radicals, some with longer lives. See the text for details. SOD, superoxide dismutase. (B) Myeloperoxidase in leukocytes can produce the reactive species hypochlorous acid and tyrosyl radical. Unpaired electrons are indicated by the dense dots and paired electrons by the light ones.

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