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Detection and Quantification of Nitric Oxide

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REVIEWS cro Detection and quantification of nitric oxide–derived oxidants in biological systems Published, Papers in Press, August 12, 2019, DOI 10.1074/jbc.REV119.006136 Matías N. Mo¨ller‡§, Natalia Rios§¶1, Madia Trujillo§¶, X Rafael Radi§¶, Ana Denicola‡§, and Beatriz Alvarez§ʈ2 From the ‡Laboratorio de Fisicoquímica Biolo´gica and ʈLaboratorio de Enzimología, Facultad de Ciencias, ¶Departamento de Bioquímica, Facultad de Medicina, and §Centro de Investigaciones Biome´dicas (CEINBIO), Universidad de la Repu´blica, Montevideo, Uruguay Edited by Ruma Banerjee ⅐ The free radical nitric oxide (NO ) exerts biological effects give rise to secondary species, many of which are oxidizing, through the direct and reversible interaction with specific tar- nitrosating, or nitrating agents toward biomolecules (1–4). gets (e.g. soluble guanylate cyclase) or through the generation of The species formed downstream from NO⅐ (i.e. NO⅐-derived oxi- secondary species, many of which can oxidize, nitrosate or ⅐ dants) include nitrogen dioxide (NO2 ), dinitrogen trioxide (N2O3), ⅐ Ϫ nitrate biomolecules. The NO -derived reactive species are typ- nitroxyl (HNO), and peroxynitrite (ONOO /ONOOH), as well as ically short-lived, and their preferential fates depend on kinetic ⅐ ⅐Ϫ hydroxyl (HO ) and carbonate anion (CO3 ) radicals formed and compartmentalization aspects. Their detection and quanti- from peroxynitrite (Fig. 1). These species are short-lived (half- fication are technically challenging. In general, the strategies lives are typically in the millisecond to microsecond range) and employed are based either on the detection of relatively stable are frequently referred to in general as “reactive nitrogen spe- end products or on the use of synthetic probes, and they are not cies.” However, this term should be used with caution because always selective for a particular species. In this study, we in a similar way as “reactive oxygen species,” with which NO⅐- describe the biologically relevant characteristics of the reactive ⅐ derived species are usually grouped, this term may give the species formed downstream from NO , and we discuss the inaccurate idea that there exists only one ill-defined species that approaches currently available for the analysis of NO⅐, nitrogen ⅐ has a particular type of reactivity and targets all biomolecules (5, dioxide (NO2 ), dinitrogen trioxide (N2O3), nitroxyl (HNO), and ؊ 6). In contrast, the different species have unique reactivities peroxynitrite (ONOO /ONOOH), as well as peroxynitrite-de- and, depending on the particular properties of each, they may ⅐ ⅐؊ rived hydroxyl (HO ) and carbonate anion (CO3 ) radicals. We lead to oxidation, nitrosation, or nitration. As a further argu- also discuss the biological origins of and analytical tools for ”,؊ ؊ ment against the use of the term “reactive nitrogen species Ϫ detecting nitrite (NO2 ), nitrate (NO3 ), nitrosyl–metal com- ⅐ ⅐ some of the species formed downstream from NO (e.g. CO3 ) plexes, S-nitrosothiols, and 3-nitrotyrosine. Moreover, we do not contain nitrogen. Finally, researchers in the nitrogen highlight state–of–the–art methods, alert readers to caveats fixation field might argue that the reactive nitrogen species are of widely used techniques, and encourage retirement of those formed in the activation of nitrogen in the nitrogenase- approaches that have been supplanted by more reliable and catalyzed process of ammonia formation. Thus, in line with selective tools for detecting and measuring NO⅐-derived oxi- proposals in the free radical research field (5, 6), we suggest that dants. We emphasize that the use of appropriate analytical the name of the identified species should be used whenever methods needs to be strongly grounded in a chemical and possible. When the species that are being referred to are biochemical understanding of the species and mechanistic unknown, we suggest using the term “NO⅐-derived oxidants.” pathways involved. The preferential targets of NO⅐-derived oxidants in biologi- cal systems are typically located in close proximity (in the ⅐ micrometer distance range) and determined by a combination Soon after the discovery of nitric oxide (NO ) as a physiolog- of factors, including kinetic aspects of rate constants multiplied ical mediator in the vascular, nervous, and immune systems, it by target concentration, compartmentalization, and membrane became evident that this moderately-reactive free radical can permeability. Some of the NO⅐-derived oxidants are good one- electron oxidants that start oxygen-dependent chain reactions in both aqueous and lipidic compartments, which may amplify This work was supported by Comisio´n Sectorial de Investigacio´n Científica the effects (1, 7). Grupos_2018 (to R. R. and A. D.), Espacio Interdisciplinario 2015 (to R. R.), ⅐ Universidad de la Repu´blica, Uruguay, and Agencia Nacional de Investi- In many cases, the formation of NO -derived oxidants is gacio´n e Innovacio´n Grant FCE_1_2017_1_136043 (to M. N. M). The linked to the presence of partially-reduced oxygen species, as authors declare that they have no conflicts of interest with the contents of exemplified by peroxynitrite, which is formed from the reaction this article. ⅐ ⅐Ϫ 1 Supported in part by a doctoral fellowship from Universidad de la Repu´blica of NO with the superoxide radical (O2 ). Thus, the formation (CAP). of NO⅐-derived oxidants is frequently related to inflammation, 2 To whom correspondence should be addressed: Laboratorio de Enzi- in which increased formation of NO⅐ through the inducible mología, Facultad de Ciencias, Universidad de la Repu´blica, Igua´ 4225, 11400 Montevideo, Uruguay. Tel./Fax: 598-25250749; E-mail: beatriz. nitric-oxide synthase converges with increased formation of ⅐Ϫ [email protected]. O2 and other oxidants. In fact, the high reactivity of some of This is an open access article under the CC BY license. 14776 J. Biol. Chem. (2019) 294(40) 14776–14802 © 2019 Mo¨ller et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. JBC REVIEWS: Analysis of NO⅐-derived oxidants fication, focusing on strategies aimed at assessing their involvement in biological processes. Nitric oxide The discovery of nitric oxide, a free radical, as an endoge- nously generated effector molecule, was a paradigm shift in biological signaling. Nitric oxide (NO⅐, IUPAC names nitrogen monoxide, oxidonitrogen(⅐), or oxoazanyl) is a diatomic free radical produced in animals mainly by the enzymes nitric oxide synthases (NOS)3. Nitric oxide has a low dipole moment (0.159 D(11)), so it has weak intermolecular interactions and it is a gas at 1 atm and 25 °C. It is only sparingly soluble in water (1.94 Ϯ 0.03 mM (12)) but is about 10 times more soluble in organic solvents (13). The partition coefficient in membrane models and human low-density lipoprotein is 4.4–3.4 at 25 °C (14). The Figure 1. Nitric oxide and its biologically relevant derivatives. Nitric oxide diffusion through cell membranes is very rapid (14–17). The ⅐Ϫ ⅐ can give rise to several species. Reaction with superoxide (O2 ) generates permeability coefficients of lipid membranes to NO range from peroxynitrite (ONOOϪ); with oxyhemoglobin (HbO ), nitrate (NOϪ); with oxy- ⅐ 2 3 18 to 73 cm sϪ1 (15, 17), similar to that of an equally thick layer gen (O2), nitrogen dioxide (NO2 ); with strong one-electron reductants, nitroxyl (HNO); with liganded iron(II) (Fe(II)L ), dinitrosyl iron complexes ⅐ 2 ⅐ of water. (DNICs); with thiyl radical (RS ), S-nitrosothiol (RSNO); and with NO2 , dinitro- ⅐ gen trioxide (N O ). Many of these products are reactive and yield further Unlike several other free radical species, NO is not a one- 2 3 Ϫ 0 ⅐ ϩ products. Peroxynitrite at neutral pH will protonate and generate NO ,as electron oxidant (E Ј (NO ,H /HNO) ϳϪ0.55 V at pH 7) (18, ⅐ ⅐ 3 well as NO and hydroxyl radicals (HO ) in 30% yield. In the presence of car- 2 Ϫ ⅐ 19). It does not abstract hydrogen atoms, and it does not add to bon dioxide (CO ), peroxynitrite will generate NO , as well as NO and car- 2 ⅐Ϫ 3 2 ⅐ bonate anion radical (CO ) in 33% yield. In the presence of reductants, per- unsaturated bonds. Importantly, NO does not react directly 3 Ϫ ⅐ oxynitrite will be reduced to nitrite (NO )orNO . Nitrogen dioxide can react ⅐ ⅐ 2 2 with thiols (RSH). Among the main targets of NO in biological with tyrosyl radicals (Tyr ) to generate 3-nitrotyrosine (NO –Tyr) or with a Ϫ 2 systems are metal centers. Coordination to the ferrous heme in reductant to form NO . Dinitrogen trioxide can be rapidly hydrolyzed to Ϫ 2 Ϫ NO2 , it can be formed by NO2 in acidic pH, and it can react with thiols (RSH) to soluble guanylate cyclase is responsible for many physiological generate RSNO. In this figure, stoichiometries are not always strict, and pro- effects of NO⅐ (20–23). Reaction with oxyhemoglobin to form tons are sometimes omitted for simplicity. Ϫ ⅐ NO3 is an important sink of NO (24, 25). Other relevant tar- ⅐ ⅐Ϫ gets of NO are other free radical species, in particular O2 (1). the species derived from NO⅐ make them part of the weaponry Nitric oxide can also react with oxygen, and this is analyzed in that immune cells use in their battles against microorganisms the next section on autoxidation. (8). In addition to their cell-damaging activity, they can have The effects of NO⅐ are exerted either via direct reactions with ⅐ signaling roles. The recognition that hydrogen peroxide (H2O2) biological targets or indirectly via NO -derived oxidants. Dys- can act as second messenger (9) and that signaling actions can regulation of NO⅐ homeostasis has been linked to neurode- be extended to species derived from NO⅐ (10) have expanded generation, cardiovascular disease, cancer, and inflammation. the traditional view of oxidative stress as a misbalance between Therefore, the detection and quantification of NO⅐ and its oxidant formation and antioxidant action to include the view of derived oxidants in vitro and in vivo are relevant to understand- a disruption in regulatory pathways.
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