Nitroxyl anion

At present, new developments challenge previous ideas concerning the role of nitric oxide in oxidative processes. The capacity of nitric oxide to oxidize substrates by a one-electron transfer mechanism was supported by the suggestion that its reduction potential is positive and relatively high. However, recent determinations based on the combination of quantum mechanical calculations, cyclic voltammetry, and chemical experiments suggest that °(NO/ NO-) = —0.8 0.2 V [56]. This new value of the NO reduction potential apparently denies the possibility for NO to react as a one-electron oxidant with biomolecules. However, it should be noted that such reactions are described in several studies. Thus, Sharpe and Cooper [57] showed that nitric oxide oxidized ferrocytochrome c to ferricytochrome c to form nitroxyl anion. These authors also proposed that the nitroxyl anion formed subsequently reacted with dioxygen, yielding peroxynitrite. If it is true, then Reactions (24) and (25) may represent a new pathway of peroxynitrite formation in mitochondria without the participation of superoxide. 

In contrast to nitric oxide, which is firmly identified in biological systems and for which numerous (but not all) functions are known, the participation of other nitrogen species in biological processes is still hypothetical. At present, the most interest is drawn to the very reactive nitroxyl anion NOT It has been shown that nitroxyl (or its conjugate acid, HNO)... 

However, the in vivo sources of nitroxyl production remain uncertain. Some authors suggested that nitroxyl anion might be generated by NO synthases [81,82] or during the decomposition of nitrosothiols [83]. It has also been proposed [81] that the primary product of NO synthase is not nitric acid but nitroxyl anion, which is next oxidized by SOD to NO ... 

It should be noted that a major difficulty in the detection of nitroxyl anion is explained by the impossibility to apply ESR spectroscopy because nitroxyl is not a free radical. Moreover, the use of spin traps such as iron iV-methyl-D-glucamine dithiocarbamate (Fe-MGD) to distinguish NO and NO production by NO synthase failed because both nitrogen species reacted with this spin trap [87]. 

As mentioned above, NO can also be reduced to the nitroxyl anion (NO-) (Eq. (5)), which is isoelectronic with 02, and like dioxygen has a triplet ground state (15). 

There is increasing interest in possible biological roles of the nitroxyl anion in both singlet and triplet forms as well as of the conjugate... 

Fig. 4. Illustration of limiting cases of NO binding to a metalloporphyrin center as (a) the nitroxyl anion (NO-) with a M-N-0 bond angle of 120° or as (b) the nitrosyl cation (NO+) with a M-N-0 bond angle of 180°.

Nitric oxide may be oxidized by one electron to give nitrosonium ion (NO ) or reduced by one electron to form nitroxyl anion (NO"), which are important intermediates in the chemistry of nitric oxide (Stamler et al., 1992a). 

Although much of the biological literature focuses on nitrosating reactions of nitric oxide, chemically nitric oxide is a moderate one-electron oxidant, making formation of nitroxyl anion feasible under physiological conditions. The reduction potential to reduce nitric oxide to nitroxyl anion is +0.39 V, whereas it requires +1.2 V to oxidize nitric oxide to nitrosonium ion. Nitrosating reactions of nitric oxide are often mediated by conversion of nitric oxide to another nitrogen oxide species or by direct reaction with transition metals (Wade and Castro, 1990). 

Nitroxyl anion has been suggested to be a potential EDRF (Murphy and Sies, 1991). However, the ttiplet state of nitroxyl anion reacts with molecular oxygen (also in a triplet state) to fotm petoxynitrite anion (Donald et al., 1986 Hughes et al., 1971 Yagil and Anbar, 1964). 

The reaction of nitric oxide with superoxide dismutase is a simple reversible equilibrium, whereas the catalytic cycle with superoxide involves a two step sequence. Consequently, superoxide dismutase may be reduced by superoxide and then react with nitric oxide to form nitroxyl anion. Nitroxyl anion may react with molecular oxygen to form peroxynitrite anion (ONOO"). 

The direct reaction of superoxide with nitric oxide is only one of at least four possible pathways that can form peroxynitrite (Fig. 40). For example, superoxide should also efficiently reduce nitrosyldioxyl radical to peroxynitrite. Alternatively, nitric oxide may be reduced to nitroxyl anion, which reacts with oxygen to form peroxynitrite. Superoxide dismutase could even catalyze the formation of peroxynitrite, since reduced (Cu or cuprous) superoxide dismutase can reduce nitric oxide to nitroxyl anion (Murphy and Sies, 1991). Thus, superoxide might first reduce superoxide dismutase to the cuprous form, with nitric oxide reacting with reduced superoxide dismutase to produce nitroxyl anion. A fourth pathway to form peroxynitrite is by the rapid reaction of nitrosonium ion (NO" ) with hydrogen peroxide. This is a convenient synthetic route for experimental studies (Reed et al., 1974), but not likely to be physiologically relevant due to the low concentrations of hydrogen peroxide and the difficulty of oxidizing nitric oxide to nitrosonium ion. 

Four routes to form peroxynitrite from nitric oxide. The reaction of nitric oxide with superoxide is only one mechanism leading to the formation of peroxynitrite. Supetoxide could also reduce the nitrosyidioxyl radical. If nitric oxide is directly reduced to nitroxyl anion, it will react with molecular oxygen to form peroxynitrite. At acidic pH, nitrite may form nitrous acid and nitrosonium ion, which reacts with hydrogen peroxide to form peroxynitrite. 

Murphy, M. E., and Sies, H. (1991). Reversible conversion of nitroxyl anion to nitric oxide by superoxide dismutase. Proc. Nad. Acad. Sci. U.S.A. 88, 10860-10864. 

Nitroxyl anion (NO-) N"=0 Can form from nonspecific donation of an electron from metals to NO ... 

H. Ohshima, Y. Yoshie, S. Auriol and I. Gilibert, Antioxidant and pro-oxidant actions of flavonoids effects on DNA damage induced by nitric oxide, per-oxynitrite and nitroxyl anion, Free Radic. Biol. Med., 25 (1998) 1057-1065. M.K. Johnson and G. Loo, Effects of egpigallocatechin gallate and quercetin on oxidative damage to cellular DNA, Mutat. Res., 459 (2000) 211-218. 

Glutathionylated proteins can be formed by the interaction of nitric oxide and protein thiols. For example, exposure of mitochondria to NO can lead to the formation of peroxynitrite, an oxidant, that can cause protein glutathionylation. Protein glutathionylation may also occur via the formation of a nitroso thiol protein (PrSNO) followed by the glutathionylate anion displacement of the nitroxyl anion (NO-) by GSH to form protein glutathionylation as shown in Figure 18.13. 

As shown in Figure 10.11, the reaction catalyzed by nitric oxide synthase is hydroxylation of arginine AT-hydroxy-arginine then decomposes to citrulline and nitric oxide. It is unclear whether the immediate product of the enzyme is nitric oxide itself or the nitroxyl anion NO the addition of superoxide dis-mutase in vitro increases the formation of nitric oxide, but this could be the... 

NO can form a molecule with an even number of electrons either by oxidation to the NO+ cation (d(N-N) 106 pm), which is isoelectronic with CO and N2 and has a nitrogen-oxygen triple bond or by reduction to form the nitroxyl anion NO, which is isoelectronic to dioxygen O2. 

The weak acid HNO (pA a = 11.4) has a singlet gronnd state (X A ). The nitroxyl anion NO has a triplet ground state (X ), therefore the dissociation of HNO to NO and H+ is spin forbidden and inherently slow. In physiological systems, HNO is the dominant form, but NO, once formed, has sufficient lifetime to react with other species. HNO is like NO a transient intermediate in physiological systems. 

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