View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1411 (1999) 263^272 Review Relationships between nitric oxide, nitroxyl ion, nitrosonium cation and peroxynitrite Martin N. Hughes * Department of Chemistry, King's College London, Strand, London WC2R 2LS, UK Received 14 August 1998; received in revised form 5 November 1998; accepted 16 December 1998 Abstract This review is concerned mainly with the three redox-related, but chemically distinct, species NO3,NOc and NO, with greatest emphasis being placed on the chemistry and biology of the nitroxyl ion. Biochemical routes for the formation of nitroxyl ion and methods for showing the intermediacy of this species are discussed, together with chemical methods for generating nitroxyl ion in solution. Reactions of nitroxyl ion with NOc, thiols, iron centres in haem and with dioxygen are reviewed The significance of the reaction between NO3 and dioxygen as a source of peroxynitrite is assessed, and attention drawn to the possible significance of the spin state of the nitroxyl ion in this context. The biological significance of nitrosation and the importance of S-nitrosothiols and certain metal nitrosyl complexes as carriers of NO at physiological pH is stressed. Some features in the chemistry of peroxynitrite are noted. ß 1999 Elsevier Science B.V. All rights reserved. Keywords: Nitric oxide; Nitroxyl anion; Peroxynitrite Contents 1. Introduction .......................................................... 264 2. The nitroxyl anion, NO3 ................................................. 264 3. Biochemical pathways for the production of nitroxyl ion . ....................... 265 4. Reactions of nitroxyl ion ................................................. 265 4.1. Reaction with metal centres to give nitrosyl complexes . ....................... 266 4.2. Reaction with thiols ................................................. 266 4.3. Reaction with the oxygen molecule ...................................... 266 4.4. Cytotoxicity of nitroxyl ion ............................................ 267 5. Chemical routes for generating nitroxyl ion . .................................. 267 6. Photochemical decomposition of trioxodinitrate ................................ 268 7. Electronic states of the nitroxyl ion . ....................................... 268 * Fax: +44 (171) 873-2810; E-mail: [email protected] 0005-2728 / 99 / $ ^ see front matter ß 1999 Elsevier Science B.V. All rights reserved. PII: S0005-2728(99)00019-5 BBABIO 44732 23-4-99 264 M.N. Hughes / Biochimica et Biophysica Acta 1411 (1999) 263^272 8. The nitrosonium cation, NO ............................................. 269 9. Peroxynitrite, ONOO3 .................................................. 269 10. Conclusions ........................................................... 270 References ............................................................... 270 1. Introduction under these conditions, the nitroxyl ion then reacts 3 3 with NO to give (NO)2 and (NO)3 [4^6]. Nitric This review deals with the relationships between oxide is also reduced to NO3 by Fe(II) in acidic the nitroxyl anion (NO3, oxonitrate(13)), nitric ox- solution, while nitroxyl ion can be oxidised to NO c 33 ide (NO , nitrogen monoxide), the nitrosonium cati- by ferricyanide ion, [Fe(CN)6] . on (NO, nitrosyl cation) and peroxynitrite Interconversion of NO3,NOc and NO can take (ONOO3, oxoperoxonitrate(13)), in which the nitro- place under cellular conditions, so all three species gen atom has formal positive oxidation states of I, II, must be considered in order to account fully for the III and III, respectively. The immense importance of biological activity of nitric oxide. The diversity and nitric oxide in the life sciences and medicine needs no complexity of such activity is consistent with the view elaboration. Peroxynitrite has also attracted consid- that various species derived from NO play important erable attention as a species through which the cyto- biological roles [7]. Indeed, NO3,NOc and NO toxic e¡ects of nitric oxide may be manifested under each exert unique toxic e¡ects on Clostridium sporo- oxidising conditions, as peroxynitrite can be formed genes [8]. by reaction between nitric oxide and superoxide ion (Eq. 1) [1]. It should be noted, however, that Fukuto and Ignarro have recently suggested that the evi- 2. The nitroxyl anion, NO3 dence supporting the presence of peroxynitrite in bio- logical systems is indirect and potentially ambiguous This review will focus on the nitroxyl ion as the and that other mechanisms may explain NO-medi- importance of this species has been overlooked or ated toxicity under oxidative conditions in vivo [2]. rejected in the past. However, it must now be ac- The species nitroxyl ion and the nitrosonium cat- cepted that nitroxyl ion can be formed in the cellular ion are related to nitric oxide by reduction and oxi- milieu by several routes and that it can exert direct dation of NOc respectively, and each has a distinctive and varied e¡ects on biological molecules and sys- chemistry unique to itself [3]. The fundamental chem- tems. Thus, it has been proposed that nitroxyl ion istry of these three species is best rationalised in may carry out reactions typical of the endothelial- terms of MO theory. The nitroxyl anion, isoelec- derived relaxing factor (EDRF), although the possi- tronic with dioxygen, has a bond order of 2. Nitric bility that nitroxyl ion is oxidised to NO before these oxide is a radical, with a bond order of 2.5, the un- reactions occur cannot be excluded. Claims have paired electron occupying an antibonding Z orbital. been made that nitroxyl ion is formed directly by Nitric oxide does not show a strong tendency to nitric oxide synthase (NOS). Furthermore, its chem- dimerise. Loss of the unpaired electron gives NO, istry and biology are linked to that of peroxynitrite which has a bond order of 3 and is isoelectronic with as the nitroxyl ion reacts with dioxygen to give per- N2 and CO. Nitric oxide is di¤cult to oxidise, with a oxynitrite (Eq. 2). This reaction occurs in the autox- reduction potential of 1.2 V. The electron a¤nity of idation of hydroxylamine in alkaline solution [9], one NOc will depend upon whether the NO3 product is route for the preparation of peroxynitrite. Several in the singlet or triplet state, but the reduction of reports have shown that co-ordination of NO to an nitric oxide to the nitroxyl ion can be carried out Fe(II) haem protein leads to reduction to give an by biological reducing agents. Nitroxyl ion is formed NO3 nitrosylhaem group which may then be fol- by reaction of NOc with hydrated electrons, although lowed by release of the nitroxyl ion. This may result BBABIO 44732 23-4-99 M.N. Hughes / Biochimica et Biophysica Acta 1411 (1999) 263^272 265 in the formation of peroxynitrite under aerobic envi- ping of nitroxyl ion by thiols has been reported ear- ronments and so this pathway must also be consid- lier by Doyle et al. [20] and Turk and Hollocher [13]. ered in any assessment of the likelihood and extent RSH of intracellular formation of peroxynitrite. The par- RSH HNO ! RSNHOH!RSSR NH2OH ent acid of the nitroxyl ion (HNO) has pKa = 4.7 and 3 so is fully deprotonated at biological pH values 3 3 2HNO ! N2O H2O 4 NO O2 ONOO 1 3 3 This reaction is important as it extends the modes NO O2 ONOO 2 of reactivity of S-nitrosothiols. These compounds Methods for the chemical generation of nitroxyl undergo homolytic cleavage to give NOc (and are ion in solution have recently been described [10]. often used as NOc releasers) although in practice they are usually more reactive as nitrosating agents (that is, they donate the NO group to an nucleo- 3. Biochemical pathways for the production of phile of appropriate reactivity). The possibility that nitroxyl ion S-nitrosothiols can also donate nitroxyl ion to thiols emphasises further the intracellular signi¢cance of It was shown some time ago by Murphy and Seiss the species formed by oxidation or reduction of that superoxide dismutase catalyses the reversible re- NOc and has consequences in terms of redox balance duction of nitric oxide to nitroxyl ion [11]. The for- that may be signi¢cant in regulatory and other proc- mation of nitroxyl ion can be con¢rmed by trapping esses. Furthermore, the hydroxylamine-producing re- with metmyoglobin (Fe(III)) [12]. action leads to the formation of S^S bonds and so As noted above, the binding of nitric oxide to could simultaneously induce conformational changes iron(II) in a haem centre may lead to the release of in enzymes or receptor sites. nitroxyl anion, which in the absence of other reac- tions will dimerise to give nitrous oxide. Examples include the nitric oxide reductase of Paracoccus de- 4. Reactions of nitroxyl ion nitri¢cans [13], cytochrome c [14] and haemoglobin [15]. In the case of cytochrome c, the released nitrox- The nitroxyl ion is a short-lived species in solution, yl ion reacted with dioxygen to give peroxynitrite, decomposing via dimerisation and dehydration to shown by the oxidation of dihydrorhodamine 123 give nitrous oxide (Eq. 4). The second-order rate [14]. In contrast to these examples of reductive for- constant for the dimerisation of HNO is 1.8U109 mation of nitroxyl ion, the oxidation of azide ion by dm3 mol31 s31 [4]. The rate of dimerisation will lignin peroxidase also leads to the release of nitroxyl vary considerably with concentration in view of the ion