Biochemistry of Peroxynitrite and Protein Tyrosine ... - ACS Publications

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Cite This: Chem. Rev. 2018, 118, 1338−1408

Biochemistry of Peroxynitrite and Protein Tyrosine Nitration Gerardo Ferrer-Sueta,†,‡,⊥ Nicolás Campolo,‡,§,⊥ Madia Trujillo,‡,§ Silvina Bartesaghi,‡,§ Sebastián Carballal,‡,§ Natalia Romero,‡,§,@ Beatriz Alvarez,‡,∥ and Rafael Radi*,‡,§ Laboratorio de Fisicoquímica Biológica, Facultad de Ciencias, ‡Center for Free Radical and Biomedical Research, §Departamento de Bioquímica, Facultad de Medicina, ∥Laboratorio de Enzimología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay

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ABSTRACT: Peroxynitrite is a short-lived and reactive biological oxidant formed from the diffusion-controlled reaction of the free radicals superoxide (O2•−) and nitric oxide (•NO). In this review, we first analyze the biochemical evidence for the formation of peroxynitrite in vivo and the reactions that lead to it. Then, we describe the principal reactions that peroxynitrite undergoes with biological targets and provide kinetic and mechanistic details. In these reactions, peroxynitrite has roles as (1) peroxide, (2) Lewis base, and (3) free radical generator. Physiological levels of CO2 can change the outcome of peroxynitrite reactions. The second part of the review assesses the formation of protein 3-nitrotyrosine (NO2Tyr) by peroxynitrite-dependent and -independent mechanisms, as one of the hallmarks of the actions of •NO-derived oxidants in biological systems. Moreover, tyrosine nitration impacts protein structure and function, tyrosine kinase signal transduction cascades and protein turnover. Overall, the review is aimed to provide an integrated biochemical view on the formation and reactions of peroxynitrite under biologically relevant conditions and the impact of this stealthy oxidant and one of its major footprints, protein NO2Tyr, in the disruption of cellular homeostasis.

CONTENTS 1. Introduction to Peroxynitrite History and Biochemistry 1.1. Early Evidence of Peroxynitrite in Biological Systems 1.2. The Question of Homolysis 1.3. Biological Formation of Peroxynitrite from Nitric Oxide and Superoxide 1.4. Formation of Peroxynitrite from the Reaction of Nitroxyl (HNO) with Oxygen 1.5. Formation of Peroxynitrite on Metal Centers 1.6. Peroxynitrite Synthesis, Quantitation, and Handling in the Laboratory 1.6.1. Peroxynitrite Administration and Exposure in Experimental Setups 2. Reactions of Peroxynitrite in Biochemistry 2.1. Kinetically Competitive Reactions 2.2. Carbon Dioxide Is the Criteria of Kinetic Competitiveness 2.3. Metal Centers in Proteins 2.3.1. Heme Peroxidases and Heme Thiolate Proteins 2.3.2. Cytochrome c Oxidase 2.3.3. Iron−Sulfur Cluster Proteins 2.4. Reduction of Peroxynitrite by Thiols and Selenols 2.4.1. Kinetic Competitiveness of Thiol and Selenol Peroxidases 2.5. Other Targets of Peroxynitrite 2.5.1. Methionine 2.5.2. Tryptophan © 2018 American Chemical Society

2.5.3. Uric Acid 2.5.4. Ascorbate 2.5.5. NAD(P)H 2.5.6. Coenzymes 2.5.7. Carbonyl Compounds 2.5.8. Ubiquinol 2.6. Fate of Peroxynitrite 2.6.1. Isomerization to Nitrate 2.6.2. Reduction to Nitrite 2.6.3. Reduction to Nitrogen Dioxide 3. Radicals and Secondary Oxidants Derived from Peroxynitrite 3.1. Carbonate Radical Biochemistry 3.1.1. Formation, Properties, and Reactions 3.1.2. Role of CO3•− in Pathophysiological Processes 3.2. Nitrogen Dioxide Radical Biochemistry 3.2.1. Formation Pathways 3.2.2. Reactivity 3.2.3. Role of •NO2 in Pathophysiological Processes 4. Tyrosine Nitration 4.1. Historical Background 4.2. Mechanisms of Tyrosine Nitration 4.2.1. General Free Radical Mechanism

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Special Issue: Posttranslational Protein Modifications Received: September 17, 2017 Published: February 5, 2018 1338

DOI: 10.1021/acs.chemrev.7b00568 Chem. Rev. 2018, 118, 1338−1408

Chemical Reviews 4.2.2. Biological Pathways of Tyrosine Nitration 4.3. Selectivity of Protein Tyrosine Nitration 4.3.1. Nitration of Nonmetalloproteins 4.3.2. Nitration of Metalloproteins 4.4. Secondary Oxidative Products of Tyrosine 4.4.1. Dimerization to 3,3′-Dityrosine 4.4.2. Hydroxylation to 3-Hydroxytyrosine 4.5. Biological Consequences of Protein Tyrosine Nitration 4.5.1. Physicochemical Properties of 3-Nitrotyrosine 4.5.2. Effects of Tyrosine Nitration on Protein Structure and Function 4.5.3. Effects of Protein Tyrosine Nitration on Cell Signaling Cascades 4.5.4. Tyrosine Nitration in the Immune Response 4.6. Metabolic Fate of Tyrosine Nitrated Proteins 4.6.1. Proteolytic Degradation of Tyrosine Nitrated Proteins 4.6.2. Metabolism of Free 3-Nitrotyrosine 4.6.3. Denitration of Tyrosine Nitrated Proteins 4.7. Structural Biology of Tyrosine-Nitrated Proteins 4.7.1. X-ray Crystallography of Tyrosine-Nitrated Proteins 4.7.2. Computational Methods 4.7.3. Other Experimental Approaches 5. Conclusions and Perspectives Author Information Corresponding Author ORCID Present Address Author Contributions Notes Biographies Acknowledgments References

Review •

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NO + O2•− → ONOO−

ONOO− + H+ ⇌ ONOOH

(1) (2)

Despite being known in the chemical literature since the beginning of the 20th century, peroxynitrite emerged in the biomedical literature in the early 1990’s,2,7−15 and since then it has been progressively identified as an important biological oxidant, playing roles as mediator in signal transduction pathways as well as in the disruption of cellular redox homeostasis.4,16,17 Among the several reactions that peroxynitrite and peroxynitrite-derived species can undergo with biomolecular targets, the nitration of protein tyrosine residues has been revealed as one of their main hallmarks. Early seminal articles in the chemical literature showed that peroxynitrous acid was capable of nitrating phenolic compounds.18 Being peroxynitrite a short-lived transient species in biological systems (ca. 1−20 ms4), protein tyrosine nitration represents its premier footprint in cells and tissues. Moreover, protein tyrosine nitration constitutes an oxidative post-translational modification that can impact in protein structure and function. Thus, this review will be presented in two parts: the first part will analyze the biochemistry of peroxynitrite, and the second part will focus on the mechanisms and consequences of protein tyrosine nitration.

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1.1. Early Evidence of Peroxynitrite in Biological Systems

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During almost 90 years of the 20th century only a few articles about peroxynitrite had been published and almost all of them were based in its unusual oxidant properties and chemical synthesis or were related to atmospheric pollution chemistry, but without any relationship with its biological role.19 It was right after the discovery of the chemical nature of the endothelium-derived relaxing factor (EDRF), finally identified as •NO,20,21 that scientists started to consider peroxynitrite as a biologically relevant molecule. In fact, the first PubMed citation using peroxynitrite as a keyword was the work of Beckman et al.,2 a paper that is a landmark of the studies about the biological role of peroxynitrite. However, several previous pieces of evidence supported the formation of peroxynitrite in biological systems, although its name or chemical nature was not appreciated or mentioned. During the 1980’s, several groups were intensely working to define the identify of a relatively unstable compound described as the endothelium-derived relaxing factor or EDRF, a molecule responsible for promoting vessel relaxation.22−26 In 1986, Gryglewsky, Palmer, and Moncada showed that the addition of the enzyme superoxide dismutase (SOD), known to catalyze the fast dismutation of O2•− (eq 3), increased the EDRFinduced relaxation of aortic rings denuded of endothelium perfused with extracellular media of endothelial cell cultures,27 suggesting that O2•− contributed to the chemical instability of EDRF.

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1. INTRODUCTION TO PEROXYNITRITE HISTORY AND BIOCHEMISTRY In the field of biochemistry, the term “peroxynitrite” encompasses the sum of two closely related species: peroxynitrite anion (ONOO−) and its conjugated acid, peroxynitrous acid (ONOOH). The IUPAC recommended names are oxoperoxonitrate (1−) and hydrogen oxoperoxonitrate, respectively. The reason for including both species in the definition of peroxynitrite stands on the fact that they coexist and are in rapid acid−base equilibrium under biologically relevant conditions (pKa = 6.8). Due to the transient nature of its precursor species and the chemical characteristics of peroxynitrite itself, establishing its formation, reactions, biochemical consequences, and relevance in biological systems represented major efforts and debates from the chemical, biological, and biomedical research communities, which finally amalgamated and settled over the past decade. The main reaction leading to the formation of peroxynitrite in biological systems is the diffusion-controlled reaction of the two radicals nitric oxide (•NO) and superoxide (O2•−) (eq 1):1−6

SOD

2O2•− + 2H+ ⎯⎯⎯→ H 2O2 + O2

(3)

An increase in the actions of EDRF was obtained in the presence of cytochrome c3+, a known scavenger of O2•− (eq 4): Cyt c3 + + O2•− → Cyt c 2 + + O2

(4)

O2•−-mediated 28

Similar results on the EDRF inactivation were also obtained by Rubanyi et al., including the observation of enhanced instability of EDRF under hyperoxic conditions. Additionally, Moncada et al. showed that redox-cycling 1339


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that cogenerate •NO and O2•− and that more closely resemble its biological formation. For example, while Radi et al.7 found that authentic peoxynitrite could induce lipid peroxidation, Hogg et al. reported that the product of O2•− and •NO could oxidize lipoproteins such as LDL and this process contributed to the pathogenesis of atherosclerosis in vivo.34,35 Another early piece of evidence of the formation of peroxynitrite in vivo came from studies about the oxidative mechanisms associated with inflammatory processes. Activation of macrophages or neutrophils promotes the assembly of the enzyme NADPH oxidase responsible for the oxidative burst and concomitant O2•− production at inflammation sites. Studies using rat lung demonstrated that vascular injury induced by immunocomplex is not only dependent on polymorphonuclear cell activation and O2•− formation but also is enhanced in the presence of L-arginine. In addition, the arginine analogue, Nγ-monomethyl-L-arginine, which blocks • NO formation, protected against the vascular injury.36 Soon after the initial proposal of its biological formation and actions,2,7,8 the discovery that peroxynitrite promotes nitration of tyrosine residues to form the stable product 3-nitrotyrosine (NO2Tyr)10,11 provided a framework to reveal peroxynitrite formation by cells and tissues. Indeed, immunochemical and bioanalytical methods allowed to rapidly advance on the knowledge of peroxynitrite formation in biological systems through the detection of protein NO 2 Tyr. In 1992, Ischiropoulos et al. demonstrated that the enzyme Cu,ZnSOD was able to catalyze peroxynitrite-mediated tyrosine nitration11 and used this readout to demonstrate that peroxynitrite can be formed by activated rat alveolar macrophages, suggesting that peroxynitrite formation may contribute to inflammatory cell-mediated tissue injury.10 A couple of years later, Beckman et al. provided another fundamental demonstration of peroxynitrite formation in vivo by detecting for the first time the presence of protein NO2Tyr in human aorta atherosclerotic lesions immunochemically.37 In the following years, and with the use of antibodies that specifically recognize NO2Tyr,38 numerous papers were published confirming the presence of NO2Tyr in diverse tissues; protein NO2Tyr was found even in healthy tissues and its levels were usually found to be significantly increased under a wide range of pathological conditions.39,40 In addition, the presence of NO2Tyr in human samples, both as a free amino acid and in proteins, was also demonstrated by mass spectrometry and other analytical techniques.16,41−45 Despite that protein NO2Tyr is established as the most relevant footprint of peroxynitrite in biological systems, it became apparent early in the field, that NO2Tyr can be also formed by nitrating species generated by peroxynitriteindependent pathways46,47 and that the sole detection of protein NO2Tyr does not necessarily equal peroxynitrite formation. There is currently total consensus that a combination of experimental approaches and measurements is required to ultimately reveal the contribution of peroxynitrite versus other nitrating systems during the generation of protein NO2Tyr in specific pathological conditions.44,48,49

compounds such as pyrogallol, that are able to generate O2•−, also inhibited EDRF-induced vascular relaxation.29 The O2•−mediated inactivation of EDRF led the groups of Moncada20 and Ignarro21 to ultimately identify EDRF as •NO. In the following years, several publications confirmed the relevance of reaction 1 in the context of vascular physiology using diverse experimental approaches. For example, when a sodium nitrite solution (containing glucose) was irradiated with UV-light immediately before perfusing a vessel, it induced vascular relaxation only if the irradiation was performed in the presence of SOD.30 The UV-irradiation induced the formation of •NO and hydroxyl radical (•OH).31 The reaction of glucose (Glc) with •OH produces then at least six different radicals by hydrogen abstraction (Glc•, eq 5),32 some of Glc• add O233 and eliminate hydroperoxyl radicals (HO2•) [i.e., the conjugate acid of O2•− also yielding a number of isomers of oxidized glucose (Glcox)]. These series of reactions provided the precursors for peroxynitrite (eq 1) and strongly diminished the half-life of • NO, preventing its arrival to the vessel-relaxation chamber. hv

glucose

NO2− + H+ → •NO + •OH ⎯⎯⎯⎯⎯⎯→ •NO + Glc•

(5)

Glc• + O2 → GlcO2 → Glcox + HO2

(6)

In these experiments, peroxynitrite was being formed secondary to photochemical rather than enzymatic reactions of •NO and O2•− production. The physiologically relevant role of O2•− in controlling EDRF half-life was clear even before knowing the chemical structure of EDRF. Once EDRF was demonstrated to be effectively •NO, the mechanism behind the inactivation observed was readily understood since reaction 1 had been previously characterized.1 However, none of these studies suggested that apart from diminishing •NO bioavailability, a product of this reaction could be biologically active. Indeed, at times the reaction of eq 1 was simplified in the physiological literature as directly leading to the formation of relatively inert nitrate (NO3−) originally regarded as the O2•−-mediated inactivation form of •NO,26 and the transient formation of peroxynitrite was not appreciated. The formation of peroxynitrite in biological systems and its potential cytotoxic role was originally postulated by Beckman et al.2 and further expanded and rationalized by Radi et al.7,8 In Beckman et al., the authors demonstrated that peroxynitrite decomposition can generate a strong oxidant with a reactivity similar to that of hydroxyl radical (•OH). They also proposed for the first time that SOD may protect vascular tissue under pathological conditions not only by preventing •NO consumption but also by preventing the formation of peroxynitrite.2 Immediately after this seminal first observation, the direct reactivity of peroxynitrite with biomolecules was established and a formal scheme showing alternative mechanisms of O2•−mediated toxicity in the presence and absence of •NO was presented.7,8 These studies also indicated that peroxynitrite could promote oxidation reactions in biological systems by direct bimolecular reactions or mediated by secondary radicals including •OH and nitrogen dioxide (•NO2). The proposed formation of •NO2 anticipated the possibility of nitration reactions associated with the biochemistry of peroxynitrite, processes that were in fact established in the next years. While the initial reports on the biochemistry of peroxynitrite implied the use of pure and concentrated peroxynitrite solutions, most of the initial results were recapitulated using chemical systems

1.2. The Question of Homolysis

The homolysis of peroxynitrous acid was the first reaction indicated as responsible for a cytotoxic role of peroxynitrite.2 The reaction happens spontaneously at neutral or acidic pH and more slowly in alkaline medium since peroxynitrous is a weak acid (pKa = 6.8). 1340


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step in the formation of protein NO2Tyr from peroxynitrite, and until the late 1990’s homolysis was the main known source of radicals. The study of the reaction with CO2 and subsequent characterization of the reaction products as carbonate radical (CO3•−) and •NO267 greatly undermined the quantitative relevance of homolysis in biochemistry. Finally, the discovery of thiol and selenol (R-SeH) peroxidases48,68,69 as fast and specialized systems for the reduction of peroxynitrite further diminished the biological significance of homolysis. In summary, homolysis is too slow (1.13 s−1 at pH 7.4 and 37 °C12) to compete with the reactions of CO2, thiol and selenol peroxidases and some transition metal centers, as will be discussed in the section of peroxynitrite reactions and kinetic competitiveness. Additionally, the formation of radicals needed for tyrosine nitration can come from other sources, such as the reaction of peroxynitrite with CO2 or with a number of metal centers, which may become kinetically competitive under different circumstances. Still, there remains the possibility that a minor fraction of peroxynitrite-derived •OH may initiate free radical-dependent processes and promote oxidations through chain propagation processes; this may well be the case in hydrophobic structures such as of biomembranes and lipoproteins where polyunsaturated lipids can be oxidized by peroxynitrite in vitro and in vivo7,14,70−72 in a way that resembles the actions of •OH.

In the absence of targets, ONOOH isomerizes to nitrate, with pH-independent rate constants of 0.1, 1.2, and 4.5 s−1 at 0, 25, and 37 °C, respectively.12,50 The isomerization reaction goes through the formation of a geminate pair of •OH and nitrogen dioxide (•NO2) radicals that either recombine in the cage to yield nitrate or diffuse to the bulk solution (Scheme 1).51 The yield of •OH and •NO2 in solution has been a matter Scheme 1. Homolysis of Peroxynitrous Acid, the Ratio kB/kA Indicates the Fraction of Radicals That Diffuse out of the Solvent Cage

of a very long debate; in fact, a number of authors considered the proposed reaction inconsistent with experimental findings and proposed alternate “activated forms” of peroxynitrite (different from the geminate pair).12,51 The nature and extent of radical formation, and the implications in its biological chemistry was the topic of discussion of an open forum published in Chemical Research in Toxicology in 1998 where the main contributors of the area collected and discussed data from reactivity and scavenging experiments, computational chemistry, thermochemistry, and kinetics.52−58 The question of homolysis has been previously analyzed in Chemical Reviews, in an article dealing with the chemistry of peroxynitrite.59 Many of the experiments and calculations designed to find out the identity and yield of the oxidants formed upon peroxynitrite spontaneous isomerization to nitrate produced ambiguous results; nevertheless, the discussions around the extent of homolysis and the species formed have continued on a purely inorganic chemistry interest. A recent and excellent review can be found in ref 60. To date, all the authors agree that peroxynitrite undergoes homolysis producing •OH and •NO2 radicals to some extent. While most of the community agrees that yields are ca. 30%,51,59 one group has repeatedly supported that homolysis is a rather small percentage, accounting for ca. 5% of the proton-catalyzed decomposition of peroxynitrite.60 In any case, product formation and yields from several different • OH scavengers, kinetic competition data and electron paramagnetic resonance experiments2,61−64 support the formation of •OH from the homolysis of peroxynitrite. Of particular interest for this review, the formation of NO2Tyr (and other oxidized forms of tyrosine) requires the intermediacy of radicals arising from peroxynitrite such as • OH and •NO2, as initially proposed in the chemical18,65 and, later, in the biochemical literature.10 Despite a long chemical debate, the homolytic pathway of peroxynitrite decay turned, after all, to be a very minor route in biological contexts and therefore of lesser quantitative and biological relevance than originally thought.4,66 Indeed, several of the authors pointed out that many reactions consuming peroxynitrite were much faster than the isomerization to nitrate. As new and faster targets were discovered, the amount of possible radicals being formed from homolysis grew smaller only considering the kinetic competition. The potential relevance of homolysis as a process accounting for the oxidative biochemistry of peroxynitrite in biological systems diminished substantially when products of the reaction with CO2 were finally characterized in 1999.67 Radical formation was a required

1.3. Biological Formation of Peroxynitrite from Nitric Oxide and Superoxide

The formation of peroxynitrite in vivo from •NO and O2•− is kinetically favored as the reaction rate constant, determined by several methodologies, is in the range of 4−16 × 109 M−1 s−1.3,5,6,73 This very large kinetic constant explains how peroxynitrite can be formed at significant rates even when the concentration of its radical precursors is low, and they, in turn, can undergo alternative reactions. The rate of peroxynitrite formation can be established as d[ONOO−] = k[•NO][O•− 2 ] dt

(7) •

Due to the favored diffusion of NO across cellular membranes74 and its longer half-life in comparison to O2•−, it can be easily predicted that peroxynitrite will be formed in the proximity of O2•− formation sites upon •NO arrival. Indeed, the anionic character of O2•− (pKa = 4.875) and its low membrane permeability confine it to the compartment where it is formed. In contrast, •NO is a small, uncharged, and nearly nonpolar molecule that freely diffuses through cellular membranes. The main constraints to the formation of peroxynitrite in biological systems that cogenerate •NO and O2•− are the pathways that consume or degrade its radical precursors. The steady-state level of O2•− in any biological compartment will depend on its rate of production and also on its decay rate, the latter largely determined by the enzyme superoxide dismutase (SOD) (eq 3). SOD is found in practically all mammalian cell compartments, at concentrations of approximately 4−40 μM Cu,Zn-SOD and 1−30 μM MnSOD in the cytosol and mitochondria, respectively.76−78 In addition, there is an extracellular isoform (EC-SOD) that shows some sequence homology to the cytosolic Cu,Zn-SOD but is specialized to function in the extracellular spaces. EC-SOD is glycosylated and secreted by the cells that produce it and binds to the extracellular matrix.79 SODs are also largely distributed in microorganisms79,80 and may decrease microbicidal perox1341


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ynitrite levels.81 All SODs catalyze the dismutation of O2•− with rate constants around (1−2) × 109 M−1 s−182−84 and effectively decrease its steady-state concentration.79,85 Although rate constant of eq 1 is larger than that of O2•− dismutation by SOD, the local SOD concentration is a key determinant of the amount of peroxynitrite that can be formed in biological systems. On the other hand, the fact that •NO can easily permeate through lipid membranes86,87 determines that its diffusion out of the compartment where O2•− is produced can become another limiting factor of peroxynitrite formation. Nitric oxide can be consumed intracellularly by reaction with other molecules or cell targets that strongly decrease the •NO half-life. In accordance with the measured rate of •NO consumption by parenchymal cells, the extravascular half-life of •NO ranges from 0.09 to >2 s, depending mainly on O2 concentration and the distance from a vessel.88 However, in the intravascular compartment •NO half-life is strongly decreased by its fast reaction with oxyhemoglobin (k = 8 × 107 M−1 s−189) that yields nitrate as the final product. The fact that hemoglobin is encapsulated slows the •NO reaction a thousand times; nevertheless, the half-life of •NO in whole blood is as short as 1.8 ms.90 In all tissues, the vasculature constitutes a major sink of •NO establishing a concentration gradient from the site of formation to the nearest vessel and hence preventing •NO accumulation in cells and tissues. The influence of the main draining pathways of •NO and O2•− (i.e., diffusion toward the vascular compartment and reaction with SOD, respectively) on peroxynitrite formation under different biological contexts is not always intuitive. For example, the effect of SOD on the steady-state concentration of • NO and on the rate of peroxynitrite production when O2•− and •NO are both being produced at comparable rates has been the subject of debate in the field for a long time. Intuition suggests that SOD will directly compete with •NO for O2•− and will therefore decrease the production of peroxynitrite.91 But, as SOD lowers the steady state level of O2•−, more •NO would be available and the product [•NO] × [O2•−] would not substantially be affected. The ability of SOD to decrease the rate of peroxynitrite production, from eq 3, will depend upon the availability of pathways that consume •NO independently of O2•−.92 Simple algebraic equations and steady state assumptions applied to model systems that considered only the presence of reactants and scavengers showed that, in general terms, the presence of SOD modestly limits the formation of peroxynitrite.91 These simplified systems did not take into account the impact of •NO diffusion, which prompted additional work emphasizing the effect of spatial distribution on peroxynitrite formation.93−96 In a mathematical model that considers a cylindrical geometry with five different concentric regions to simulate a blood vessel, the formation and chemical reactions of the peroxynitrite radical precursors •NO and O2•−93 and also the diffusion properties of •NO as well as oxygen partial pressure gradients,93 it was possible to quantitate how competition between O2•− scavenging by •NO and the SOD-catalyzed removal varied spatially. An interesting prediction of this work was that while in the vascular compartment, the highest •NO levels are expected to be near the endothelium; the maximum peroxynitrite concentration occurs deeper in the vascular wall or perivascular tissue. Another computer-assisted kinetic model to simulate peroxynitrite formation and peroxynitrite-dependent tyrosine

nitration under biological conditions was developed.96 In this model, •NO diffusion outside the compartment where it is being formed was also included as an additional kinetic process partially responsible for •NO disappearance. The rate of consumption due to diffusion depended mainly in the distance between the compartment and the nearest vessel where •NO concentration decayed to zero; but the model could also be applied to other conditions where •NO concentration decay was due to cell consumption. It was concluded that when SODcatalyzed O2•− dismutation and •NO decay due to diffusion are incorporated in the model, the steady-state concentrations of • NO and O2•− do not significantly change with variations in the relative fluxes of formation of the radicals. The absence of sensitive probes that directly react with peroxynitrite have made difficult the validation of these theoretical models until recently. In fact, most of the experimental studies analyzing peroxynitrite formation yields from fluxes of •NO and O2•− relied on the measurement of reactions of peroxynitrite derived radicals, such as NO2Tyr. The use of NO2Tyr as a marker of peroxynitrite formation has provoked a series of confounding interpretations regarding the yields of peroxynitrite formation under different fluxes of • NO and O2•−. Studies in biochemical systems varying the fluxes of either •NO or O2•− yielded a bell-shaped profile with maximun NO2Tyr yield at equimolar fluxes of both precursors. These observations were initially hard to reconcile with in vivo data where NO2Tyr yields seemed to increase under conditions where either O2•− or •NO formation was increased and even argued against peroxynitrite as the mediator of tyrosine nitration in vivo.97 However, this biphasic response with maximum yields of NO2Tyr at equimolar ratios is lost when the role of the draining pathways of •NO and O2•− present in cells and tissues are considered. Computer-assisted simulations demonstrated that the inhibition of NO2Tyr yields under excess of formation of any of its precursors was due to the competing reactions of both •NO and O2•− with radical intermediates of the nitration mechanism, mainly with tyrosyl radicals and •NO2. Nevertheless, when considering heterogeneous and compartmentalized biological systems in the presence of catalytic sinks and transmembrane diffusion that allow elimination of the excess precursor radicals, •NO and O2•− concentrations are much lower and resistant to variations. In those cases, competing reactions with nitration intermediates are not significant,96 and the decrease in nitration yields with an excess of precursor flux is not observed. Similar inhibitory responses of target oxidation in vitro by variation of O2•− or • NO fluxes were observed during lipid peroxidation98 and probe oxidation studies97,99−101 in processes that are initiated by peroxynitrite-derived radicals. The recent incorporation of boronate-derived probes that react fast and stoichiometrically with peroxynitrite102,103 (Scheme 2) provided strong evidence that peroxynitrite formation increased linearly and reached a plateau with a 1:1 ratio of cogenerated •NO and O2•− fluxes.102 In a recent study, using boronate-derived probes in a model of murine macrophages activated for •NO and O2•− production, the effect of • NO diffusion and O2•− compartmentalization on peroxynitrite formation was addressed experimentally104 and confirmed that the bell-shaped profiles obtained in vitro when NO2Tyr was used as a marker of peroxynitrite formation were a confounding observation not extrapolable to in vivo systems. In addition to the boronate-based chemical probes, genetically encoded 1342


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Since O2 has a triplet ground state, its reaction with 3NO− is spin-allowed and forms peroxynitrite with a rate constant of 2.7 × 109 M−1 s−1.115 Nevertheless, the slow deprotonation of HNO determines that, in biological systems, 3NO− will not be formed, and reactions of HNO with suitable targets will prevail. The situation could be different in the presence of systems with the potential to generate 3NO− in the presence of oxygen, but biological studies involving nitroxyl donors (e.g., Angeli’s salt) most likely involve the protonated HNO species and lead to reactions only related to HNO. In contrast to the fast reaction of 3O2 with 3NO−, the reaction with 1HNO is spin-forbidden and relatively slow. The rate constant was estimated to be 8 × 103 M−1 s−1118 and 3 × 103 M−1 s−1,119 while a more recent determination gave a slightly higher value of 1.8−2 × 104 M−1 s−1 at pH 7.4.120 The species that is formed from the reaction of HNO and O2 has been the subject of some controversy, and it has been argued that a species distinct from peroxynitrite is formed.119,121 Nevertheless, a recent study using boronate-based probes provided strong evidence for the formation of authentic peroxynitrite.120 Still, the biological relevance of the formation of peroxynitrite from the reaction between HNO and O2 can be questioned on kinetic grounds. From the rate constant and tissue O2 concentrations, which are relatively low, and from the presence of high concentrations of alternative targets (e.g., thiols and metal centers) that react with HNO with high rate constants, it becomes clear that formation of peroxynitrite in vivo from the reaction between HNO and O2 is negligible. For example, the reaction between HNO and glutathione, which is present in millimolar concentrations inside cells, has a rate constant of 3.1 × 106 M−1 s−1.120 In addition, HNO can dimerize yielding nitrous oxide (N2O) (8 × 106 M−1 s−1).117 Thus, the reaction between HNO and O2 to form peroxynitrite may only be of some significance in vivo in well-oxygenated systems with decreased thiol content; although, undoubtedly, this reaction needs to be taken into account in in vitro studies.120 In summary, although the reaction of O2 with triplet NO− to form peroxynitrite is very fast, the presence of triplet NO− in biological systems is improbable. The formation of singlet HNO is more probable, but its reaction with O2 is spinforbidden and relatively slow, making formation of peroxynitrite through this pathway in vivo unlikely.

Scheme 2. Boronate-Based Probes Detection of Peroxynitritea

a

The probe is an arylboronate that may be forming a cyclic 1,3,2 dioxaborolane structure through a bond between R1 and R2. Upon reaction with peroxynitrite, the reporter/tag moiety yields a phenolic compound suitable to spectroscopic or affinity detection. The secondorder rate constant of peroxynitrite with these probes is on the order of 106 M−1 s−1 at pH 7.4 and 37 °C. The probes also detect other oxidants such as hydroperoxides and hypochlorite. Importantly, the rate constant of peroxynitrite with, for example, fluorescein boronate is about a million times larger than that with H2O2 and 2700 times larger than that of HOCl; these significantly different rate constant values provide a large kinetic advantage for peroxynitrite detection.103,107,108

versions of green fluorescent protein-containing the unnatural amino acid p-boronophenylalanine have been recently reported and show high specificity for peroxynitrite detection.105,106 Two thorough analyses of boronates and other chemical probes for the detection of peroxynitrite (or peroxynitrite-derived radicals) have been recently published elsewhere.107,108 1.4. Formation of Peroxynitrite from the Reaction of Nitroxyl (HNO) with Oxygen

A second potential pathway for peroxynitrite formation could be the reaction of O2 with HNO (nitroxyl, nitrosyl hydride, hydrogen oxonitrate, and azanone). The chemistry involved is complex, and the reaction is dependent on deprotonation and on spin state. There are comprehensive reviews about HNO in the literature.109−113 HNO is the one-electron reduction product of •NO (E°′ • NO, H+/HNO ≈ − 0.55 V at pH 7).114,115 HNO can be exogenously administered with donor compounds such as Angeli’s salt and Piloty’s acid. It is also possible that it is formed endogenously and exerts signaling effects; this possibility still needs to be unequivocally demonstrated. The pathways proposed to be involved in HNO formation in vivo have been recently reviewed116 and include the incomplete oxidation of arginine by nitric oxide synthase, the oxidation of hydroxylamines by heme proteins, and the reduction of •NO by enzymes (SOD, xanthine oxidase), thiols, hydrogen sulfide, vitamin C, and aromatic alcohols. The ground state of HNO is a singlet, but its conjugated base [NO−, nitroxyl anion, oxonitrate (1−)] has a triplet ground state with two unpaired electrons and is isoelectronic with O2. The reduction of •NO to triplet NO− is even more unfavorable than the reduction to HNO, since the E° (NO•/3NO−) is ∼ −0.8 V.114,115 The pKa of HNO was reevaluated and is 11.4, not 4.7 as previously thought.114,115 This has important biological consequences, since it reveals that HNO is the only species that is present at physiological pH. Furthermore, the acid−base equilibrium of HNO is a slow process since it is spin forbidden; it can be represented by eq 8. HNO + OH− ⇌ 3 NO− + H 2O

1

1.5. Formation of Peroxynitrite on Metal Centers

One possible route of biological peroxynitrite formation that has attracted some attention over the last decades involves the reaction of the radicals •NO and O2•− with one of them being bound to a metal center. As early as 1981, it was proposed that the reaction of oxymyoglobin and oxyhemoglobin with •NO produced an O-bound peroxynitrito complex (Scheme 3a).122 Peroxynitrite thus formed has been invoked in several studies of • NO oxidation by these proteins.122−126 As a matter of fact, it has been proposed that the •NO dioxygenase activity of oxymyoglobin and oxyhemoglobin constitutes a primal function for the hemoglobin superfamily; this was suggested based on the evolution of hemoglobins from the microbial flavoHb that bacteria use as protection against •NO toxicity.127 Under this optic, the peroxynitrite formed would only be released after isomerization to nitrate which explains the strict 1:1 • NO:NO3− stoichiometry observed in the reaction.122 Spectrophotometric evidence of peroxynitrite formation was shown at pH = 9 in the reaction of oxymyoglobin with •NO, and even

(8)

In contrast to typical acid−base reactions, that are very fast, the deprotonation of HNO is relatively slow with forward and reverse rate constants for eq 8 of 4.9 × 104 M−1 s−1 and 1 × 102 s−1, respectively, because of the requirement for nuclear reorganization and spin change.117 Thus, contrary to typical conjugate pairs, HNO and NO− will not be in fast equilibrium. 1343


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Scheme 3. Metal Peroxynitrito Complexes Can Be Formed from O2 or •NO Bound to a Metal Center, Typically a Heme Protein, The Reactions Yield the (a) O-bound and (b) N-bound Complexes, Respectivelya

a In the case of proteins of the hemoglobin superfamily, the complex catalyzes the isomerization of O-bound peroxynitrite to nitrate prior to the dissociation. Other heme proteins can sustain the homolysis to •NO2 and even promote site specific protein nitration.

some •OH release was hinted by the oxidation of ethylene to ethylene glycol when the reaction was performed under argon.123 Another possible formation of peroxynitrite bound to a metal center involves the reaction of a nitrosyl complex with oxygen that would lead to a N-bound peroxynitrito complex (Scheme 3b) that has been proposed for nitrosylmyoglobin,128 nitrosylcobalamin,129 and more recently cystathionine β-synthase.130 Most of the reported peroxynitrito compounds have been spectroscopically characterized to different extents. Additionally, there are several examples of metal peroxynitrito compounds coming from the bioinorganic chemistry literature.131 One crucial point to consider in these potential alternative routes to peroxynitrite formation is that in many cases, metal bound peroxynitrite tends to isomerize or homolyze before dissociating from the metal, thus leading to a different kind of chemistry, as has been recently pointed out.132 Finally, there is at least one report of an enzymatic nitration reaction specifically catalyzed from peroxynitrite formed in situ, O-bound to a heme thiolate in a Streptomyces spp. cytochrome P450.133

eliminated by adding manganese dioxide (MnO2), which catalytically decomposes hydrogen peroxide. It is also important to control the preparations for the level of contaminant nitrite, because it can by itself generate confounding results; on one hand, nitrite can react with peroxynitrite-derived •OH and yield •NO2 (in fact excess NO2− can be used as a strategy to convert all radicals arising from peroxynitrite homolysis to •NO2144) or have bioactive effects.145−152 Thus, ideally, peroxynitrite preparations for biochemical and cellular experiments should contain negligible amounts of H2O2 (after MnO2 treatment), NO2− below 10% of peroxynitrite content and low carbonate contamination from air exposure of the alkaline stock solution. To control for the effect of contaminants, it is good practice to perform the so-called “reverse order of addition experiments”, where peroxynitrite is decomposed in the buffer prior to the experiments. One major issue in the experimental design involving peroxynitrite is the selection of the buffer system, phosphate being the first choice. Many of the buffers utilized for performing biochemical assays such as tris and hepes can either react with peroxynitrite or peroxynitrite-derived radicals and yield products (e.g., H2O2, nitroso compounds, •NO donors)153−156 that can secondarily affect the experimental outcome. Thus, the use of organic buffers should be avoided if at all possible. The concentration of peroxynitrite anion can be conveniently followed at 302 nm, and therefore alkaline stock solutions are utilized for peroxynitrite quantitation previous to experiments. The absorption coefficient of peroxynitrite anion was initially measured to be ε = 1670 ± 50 M−1 cm−1.157 The value was later confirmed to be precisely ε = 1700 ± 10 M−1 cm−1.143 1.6.1. Peroxynitrite Administration and Exposure in Experimental Setups. Peroxynitrite is labile, as discussed previously, even if alone in neutral solution it decays by homolysis/isomerization to nitrate (Scheme 1). In the laboratory, the exposure of biochemical systems to peroxynitrite can be performed through the addition of peroxynitrite itself, either as a bolus or as a continuous infusion, or through the simultaneous generation of its precursor radicals, O2•− and • NO. The final outcome may turn out to be different due to the possible involvement of free radicals in parallel processes. The bolus introduction of a high (sometimes millimolar) concentration of peroxynitrite can, in the absence of efficient scavengers, lead to relatively high concentrations of radicals and hence to high rates of radical−radical termination reactions in comparison to competing reactions of the free radicals with nonradical targets. In contrast, the slow infusion of peroxynitrite leads to lower steady-state free radical concentrations and hence to lower rates of radical−radical reactions.

1.6. Peroxynitrite Synthesis, Quantitation, and Handling in the Laboratory

Several procedures for synthesizing peroxynitrite in the laboratory have been designed (a) from acidified hydrogen peroxide and nitrite,2,134−136 (b) from the reaction of azide and ozone,137 (c) from the autoxidation of hydroxylamine,138 (d) from alkaline hydrogen peroxide and alkylnitrites,139,140 (e) from •NO gas and solid KO2 in sand,141 and (f) from •NO gas and tetramethylammonium superoxide in liquid ammonia.142,143 This last method stands out as the cleanest one. It produces solid tetramethylammonium peroxynitrite free of contaminants. The first method mentioned, the synthesis from acidified hydrogen peroxide and nitrite, is the method more often used. This method involves the nitrosation of hydrogen peroxide according to eqs 9 and 10. HNO2 + H+ ⇌ H 2O + NO+

NO+ + H 2O2 → ONOOH + H+

(9) (10)

The reaction is carried out by mixing hydrogen peroxide in hydrochloric acid with sodium nitrite in a flow reactor with efficient mixers. Since the peroxynitrous acid formed is unstable, the reaction is quenched with sodium hydroxide. Peroxynitrite anion is obtained in variable yields and contains sodium chloride, sodium hydroxide, hydrogen peroxide, nitrite, and nitrate as contaminants. Hydrogen peroxide can be 1344


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Figure 1. Different scenarios cause different exposure to peroxynitrite measured as the area under the curve (AUC) of the time course of the concentration. The decay of 1 mM peroxynitrite in phosphate buffer pH = 7.4 and 25 °C produces an exposure of 3.85 mM s in a spectator target (A). If the solution contains 1.3 mM CO2 then the decay is much faster and the exposure reduces to 25.7 μM s (B). A flux of 16.7 μM/s during 10 min, equivalent in total amount to the 1 mM bolus, produces a slightly larger exposure of 3.96 mM s (C). In microheterogeneous systems such as cells in suspension or liposomes, exposure inside and outside differ due to permeation of the membrane and different targets inside and outside the cell. A 1% (V/V) cell suspension mimicking the size of T. cruzi (2 μm average radius) subject to a 1 mM bolus of peroxynitrite in inert buffer at pH 7.4 has an outside exposure of 1.8 mM s (D), whereas the inside experiences an exposure of only 1.12 μM s, inset, detail of the buildup of peroxynitrite in the first milliseconds after the bolus (E). Numerical integration of the peroxynitrite time course inside vesicles of different sizes exposed to bolus of 1 mM (black ■) or 100 μM (blue ■) or fluxes of equivalent amount (1.67 μM/s during 10 min green ● or 0.167 μM/s during 100 min red ●). As a comparison, the measured values of peroxynitrite exposure inside an ionomycine-activated endothelial cell during 90 min (blue ▲) and inside T. cruzi cell phagocytosed by a macrophage during a 90 min respiratory burst (green ▼). The independent variable kD[Ves] is inversely proportional to the square root of the radius of the vesicle, representative sizes of cell types and liposomes are depicted as vertical lines.

μM/s during 10 min would be needed to approximately equalize the exposure of the 1 mM bolus, implying that a continuous flow is slightly more efficient than a bolus in terms of exposure (Figure 1C). That is for a homogeneous system, a microheterogeneous system such as a cell suspension represents additional complexity. Three processes are important in such a situation: diffusion, permeation, and chemical reactions. The rate of diffusion-controlled encounters between peroxynitrite and liposomes or cells in suspension can be estimated using the Einstein−Smoluchowski model159 (eq 13)

Measuring the exposure of a target to peroxynitrite depends substantially on the experimental setup, the pH, and the presence of other targets. To compare different scenarios, we can assume a spectator target that could consume a minimal fraction of total peroxynitrite and with a slow rate to avoid altering the decay. The simplest case would be a solution of peroxynitrite in pH = 7.4 buffer that only considers the decay via homolysis/isomerization to nitrate. Under those conditions, a single bolus of 1 mM peroxynitrite decays exponentially with k = 0.26 s−1 at 25 °C according to eq 11: [ONOO−]t = [ONOO−]0 exp(−kt )

(11)

kD = 4000πNrABDAB

The exposure (i.e., the concentration experienced by the spectator along the decay) can be calculated as the integral of peroxynitrite concentration as function on time158 (eq 12).

∫0

∞

[ONOO−] dt =

−[ONOO−]0 exp(−kt ) k

∞

= 0

(13)

where kD is the rate constant of diffusion-controlled encounters, N is the Avogadro constant, rAB is the sum of the radii of the cell and peroxynitrite (essentially equal to the average radius of the cell), and DAB is the sum of the diffusion coefficients of the cell and peroxynitrite (essentially equal to the diffusion coefficient of peroxynitrite). By multiplying kD times the concentration of vesicles (liposomes, cells, etc.) a pseudo-first order decay constant is obtained, kD[Ves]. Permeation is more complex, it implies the permeability constant PONOOH of peroxynitrous acid through a given barrier (e.g., a cell membrane) competing with desorption (i.e., the rate at which peroxynitrite can go back to the bulk solution once it reached the membrane interface). There are a few determinations of permeability on liposomes in the literature all around PONOOH = 1 × 10−3 cm/s,160−162 that, combined with a membrane width of 5 nm, yields a transmembrane diffusion

[ONOO−]0 k

(12)

The integral (i.e., the area under the curve of the time course) is then 3.85 mM s (Figure 1A). Just in order to compare, if the same experiment is made in the presence of 1.3 mM CO2 to intercept the peroxynitrite, then k = kapp[CO2] = 39 s−1 and the exposure of the spectator only 25.7 μM s (Figure 1B). If peroxynitrite is added as a continuous flow injection, the function describing the time course is not so simple but can be simulated in any computational kinetics program and numerically integrated. A simple calculation tells that an influx of 1.5 1345


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constant kt of 2 × 103 s−1. The desorption rate constant kDes has been determined based on experimental data of permeation by the group of Hurst.160 Finally, as there are two compartments (outside and inside), two sets of chemical reactions need to be considered. For the sake of simplicity, the assumption is made that peroxynitrite only decays via homolysis/isomerization outside and via a pseudo-first-order process inside that involves the reaction with carbon dioxide and the most relevant catalytic antioxidants such as peroxiredoxins and glutathione peroxidases (see below). The overall scheme is depicted in Scheme 4 based on a similar approach previously published.160

Another interesting feature is that the exposure becomes independent of diffusion when the vesicles or cells are small enough and concentrated enough as to make kD[Ves] ≫ kiso. On the other hand, large cells such as granulocytes are in smaller numbers even when occupying 1% of the volume (ca. 5.6 × 106 cells/mL) and diffusion becomes a limiting factor. It has been repeatedly observed in the literature that extracellular CO2 actually protects cells from exposure to peroxynitrite.165−169 In the light of the diffusional-kinetic model, it is easy to see that anything that consumes peroxynitrite extracellularly and transforms it into a shorterlived oxidant (e.g., CO2 yielding CO3•−) would impose an additional competition to the diffusional encounter, thus diminishing the amount of ONOOH actually reaching the cell and permeating the membrane. Thus, CO2 in vivo helps focus the reactivity of ONOO− to a very narrow region. In this context, CO2 becomes an “extracellular protectant” in systems where diffusion is a contender, such as cell suspensions or bacteria in plasma. On the other hand, in phagocytosed cells, distances are too small for chemical reactions to compete with diffusion and, in those cases, extracellular CO2 would not protect from exposure to ONOOH and may change the type of extracellular oxidants to include CO3•−. A large number of caveats must be considered after this mathematical consideration of the diffusion−kinetic fate of peroxynitrite, the most important are (1) only peroxynitrite is taken into account, the exposure to its decay products (radicals, nitrite, etc.) is never considered. For example, •NO2 readily permeates membranes170 and may enhance transmembrane oxidation. (2) Transmembrane permeation of ONOOH is taken as equal to that measured in liposomes, permeation of ONOO− is not considered even when it is known that ONOO− can enter cells through anion channels;171,172 additionally, membranes are taken as symmetrical, with kt equal in both directions. (3) The consumption of peroxynitrite by antioxidant enzymes is considered to be constant even in cases where the oxidative insult is sustained and prolonged, (i.e., phagocytosed T. cruzi during 90 min of respiratory burst).173 (4) Damaging effect on the membrane that may alter is permeability, (e.g., as a byproduct of extracellular •OH and • NO2 production) is not considered. (5) This approximate model can only estimate the effect of ONOOH to cells in suspension, adherent cells constitute a different diffusional challenge that was not approached here. Aside from all these considerations, the numerical calculations provide a rough estimate of the exposure inside a suspended cell subject to a bolus or a flux of peroxynitrite and the values obtained are on the same order of magnitude of experimental values of cell-produced peroxynitrite.103 As a conclusion, a bolus of 1 mM peroxynitrite, that could be considered very large for more stable oxidants such as H2O2 or HOCl, is within the range of biological exposure to peroxynitrite experienced in cell models.

Scheme 4. Pathways of Peroxynitrite Diffusion, Permeation, and Reaction in and out of a Cell or Vesicle in Suspensiona

a kiso is the rate constant of homolysis/isomerization at a given pH, kD[Ves] is the diffusion-controlled encounter rate constant times the concentration of vesicles, kDes is the desorption rate constant,160 and kapp[T] is the pseudo-first order rate constant of peroxynitrite consumption inside a cell, a typical value being 500 s−1.66,163 kt is the transmembrane permeation rate constant, obtained as kt = PONOOH/d, where d is the bilayer width, typically 3−5 nm.

The kinetic simulations of the fate of peroxynitrite in such a system can be done considering different boluses and fluxes. To illustrate the point, a further assumption is made that a constant volume of the system (1%) is occupied by the cells or vesicles with variations in their size, to mimic different cell types. Several studies have exposed different cells in suspension to peroxynitrite boluses, for instance, red blood cells164 and Trypanosoma cruzi.158 As an in depth example, we will discuss the situation assuming a 2 μM-radius cell in suspension, mimicking T. cruzi, a model that has been studied in our laboratory.165 A 1% volume suspension of such cells equals a count of 3.2 × 108 cells per milliliter or 538 fM. When exposed to a 1 mM bolus of peroxynitrite (pH 7.4, 25 °C), approximately half is consumed outside by homolysis/ isomerization (outside exposure 1.81 mM s, Figure 1D). The other half is consumed inside by enzymatic antioxidants, mainly enzymatically by peroxiredoxins, and nonenzymatically by CO2, with an aggregate kapp[T] ≈ 500 s−1.66,103,163 Therefore, owing to the faster consumption inside, the exposure of a spectator target inside would be much lower (1.5 μM s) than outside (Figure 1E). Comparison of those estimates with previously measured intracellular data of peroxynitrite103 in terms of exposure shows that a 1 mM bolus of peroxynitrite in pH 7.4 inert buffer is within the same order of magnitude to the situation encountered in ionomycin-stimulated endothelial cells and well below the exposure that T. cruzi undergoes inside the phagosome of activated macrophages103 (Figure 1F).

2. REACTIONS OF PEROXYNITRITE IN BIOCHEMISTRY Three types of reactions can encompass the whole biochemistry of peroxynitrite. It can act as an oxidant by bimolecular nucleophilic substition (SN2) and electron transfer (ET) mechanisms, or it can act as a Lewis base to form transient Lewis adducts that have a reactivity of their own. This minimalistic summary veils all the details and complexity but serves as a starting point. As we will soon see, the chemical mechanisms of the reactions are not essential but the rates at 1346


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2.1. Kinetically Competitive Reactions

which the reactions occur should be the cornerstone of the discussion of peroxynitrite biochemistry. Almost since its emergence as a biomolecule, targets for peroxynitrite reactions accumulated. A quick glance to the literature in the early 1990’s reveals numerous molecules that either reacted with or were somehow modified by peroxynitrite. This ever growing list of putative targets included also a large number of artifactually modified molecules (i.e., molecules that did not react at any measurable rate with peroxynitrite but that reacted with decay products formed from it in the experimental setup). Low molecular weight compounds,8,12,174−181 proteins,8,9,182−193 and even lipids,7,34,194,195 carbohydrates,196 and nucleic acid components197−199 appeared as possible targets constituting a plethora of modifiable biomolecules. Potential biotargets for peroxynitrite were accumulating in the literature, either as possible scavengers/protective agents or as ultimate recipients of oxidative damage through which peroxynitrite could “exert its toxic effects”. Very often, studies on molecular modifications due to peroxynitrite lacked contextualization; the knowledge of the chemical composition of the biological compartment where the putative reactions take place can indicate their likelihood of happening at all. It is clear that not every molecule that could react with peroxynitrite has the same quantitative relevance as a scavenger or target, and the discerning criterion is reaction kinetics. Early studies of peroxynitrite biochemistry evidenced that faster reactions would be more likely,166,200 and a few candidates to be the main peroxynitrite consumers soon stepped forward. We will describe the current knowledge of the biological targets of peroxynitrite based on a few simple assumptions. (1) Acid−base equilibria are fast. (2) Reactions take place with rates similar as those in dilute solution. (3) Reactions consuming peroxynitrite are fast, therefore its steady-state concentration is very low. Peroxynitrite disappears from a biological compartment either via chemical reactions or by diffusion and permeation through membranes. The chemical consumption of peroxynitrite can be understood as a sum of numerous parallel reactions, each contributing to the overall consumption rate according to the equation: −

d[ONOO−] = [ONOO−]ss dt

∑ knapp[Tn]

In accordance with the current knowledge of peroxynitrite reactions, a few targets account for the vast majority of its consumption, but their presence and concentrations depend greatly on the compartment being considered. Carbon dioxide, peroxidases (both heme and selenol/thiol-dependent), and a few metalloproteins are responsible for most of peroxynitrite consumption in vivo. In the next sections, we will provide details of these chemical reactions and we will describe parameters that allow assessing the quantitative importance of a given target for the consumption of peroxynitrite. 2.2. Carbon Dioxide Is the Criteria of Kinetic Competitiveness

The reaction between peroxynitrite and carbon dioxide was first hinted in 1969 by Keith and Powell50 and later substantiated through the change in reactivity that bicarbonate buffers imposed on peroxynitrite-mediated reactions.202 Later on, the reaction was found to occur strictly between ONOO− and CO2 and not other acid−base species.178 The pH-independent rate constant for the reaction was measured as k = 3 × 104 M−1 s−1 (25 °C)178 or 5.8 × 104 M−1 s−1 (37 °C).203 The first reaction product was proposed to be the short-lived adduct ONOOCO2−,202 but this species has never been detected because through rapid homolysis, it yields nitrogen dioxide and carbonate radicals (•NO2, CO3•−). The existence of two intermediates in the reaction, namely ONOOCO2− and the radical pair, was ascertained by kinetics and yield analyses using several probes such as metal complexes, tyrosine, and iodide.204,205 The short life of ONOOCO2− implies that it is not scavengeable because its transformation to the geminate pair [CO3•−, •NO2] is faster than any bimolecular reaction. The geminate pair could recombine in the solvent cage to produce carbon dioxide and nitrate, or diffuse out as free radicals;204,206,207 the reaction rates (kA and kB in Scheme 5) of Scheme 5. Sequence of Reactions between ONOO− and CO2a

(14)

a

The rate-limiting step in the sequence is the formation of ONOOCO2−. The ratio kA/kB is approximately 2, which implies that approximately one third of the radicals are scavengeable. The fact that carbon dioxide is reformed at the end of the reaction explains why some authors refer this sequence as the CO2-catalyzed isomerization of peroxynitrite.209 Such catalysis is only possible in vitro and in the absence of scavengers of CO3•− and •NO2.

where [Tn] is the concentration of a target that reacts with an apparent second-order rate constant knapp. Therefore, the product of target concentration times its respective rate constant will represent the quantitative significance of its reaction in the context of all the concurrent reactions. Alternatively, one can define the fraction of peroxynitrite consumed by a specific target Ti as the ratio:

ΦTi =

kiapp[Ti ] ∑ knapp[Tn]

the two processes have a ratio of approximately 2:1, therefore, at most one-third of the original peroxynitrite can be trapped as nitrogen dioxide and carbonate radical. Carbonate radical as a reaction intermediate has been unambiguously identified by continuous-flow EPR.67,208 The simplest reaction sequence accounting for all experimental findings is presented in Scheme 5. The reaction with CO2 is quantitatively one of the most important in accounting for peroxynitrite consumption. The product kapp[CO2] is relatively high, and additionally, carbon dioxide is an ubiquitous target, so this reaction is ideal to set a reference value for the rest of the kinetic contributions; we have

(15)

Calculating the overall rate of peroxynitrite consumption or the fraction corresponding to each target requires a thorough knowledge of the chemical composition of the compartment of interest and of the reaction kinetics for each target. This kind of kinetic analyses has been done a number of times in the peroxynitrite literature in the past 20 years with increasing number of targets.57,66,201 1347


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previously proposed kapp[CO2] = 60 s−1 as a benchmark value that considers cytosolic-like conditions (Figure 2).66 Never-

Both routes of equilibration are rather slow at neutral pH, but carbonic anhydrases, which are widely distributed and extremely efficient enzymes,212 catalyze reaction 18 and help the system approach equilibrium in vivo. Additionally, different intracellular compartments have different pHs, but CO2 permeates easily across membranes. Finally, there is the question of CO2 gradients due to formation and consumption sites. The assumption that all species are in equilibrium yields the line plots shown in Figure 2 for kapp and [CO2]. Those allow a first approximation to kapp[CO2] values (blue ■) in which kapp[CO2] ranges from 17 s−1 for mitochondrial matrix to 129 s−1 for Golgi. Another set of assumptions considers that mitochondria are the main source of CO2, and they typically have a net outflux of CO2 through membrane permeation,213 thus the mitochondrial [CO2] should be higher than cytosolic [CO2] to establish a favorable gradient. Under those assumptions, we could calculate a mitochondrial kapp[CO2] ≥ 72 s−1. Overall, the mitochondrial [CO2], and therefore kapp[CO2], could have variations depending on the metabolic commitment of decarboxylation reactions, urea synthesis, and mitochondrial carbonic anhydrase activity but within the aforementioned range of values (i.e., 20−70 s−1). Other targets reacting with peroxynitrite should have kapp[T] not too far below the reference values for CO2 (Figure 2) in order to be considered kinetically competitive. In the following section, we will refer to the current knowledge of peroxynitrite reactions always considering that all reactions are concurrent with the reactions in Scheme 5 and thus competing kinetically with it.

Figure 2. pH effect on CO2 concentration and the rate constants of its reaction with ONOO − . Dotted line (left axis), equilibrium concentration of CO2 based on normocapnic values (PaCO2 40 mmHg, HCO3− 25 mM). Continuous line (right axis), calculated kapp values based on pKa′(CO2) = 6.02,210 pKa (ONOOH) = 6.88, k = 5.8 × 104 M−1 s−1 (37 °C).203 Squares and the values below them represent kapp[CO2] (s−1) for three intracellular compartments of different pH.214 The value in the light blue circle assumes that CO2 equilibrates across the mitochondrial membrane and thus [CO2] is the same in the mitochondrial and cytosolic compartment.

2.3. Metal Centers in Proteins

The chemistry of peroxynitrite reacting with transition metal centers in proteins is complex and intricate both in terms of reaction rate constants and of the numerous possible products formed. Since the first published articles of peroxynitrite reaction with metal proteins,183 it was evident that even closely related proteins such as myeloperoxidase and lactoperoxidase differed in rate constant and product distribution. Other hemeproteins with a nonperoxidatic main function, such as oxyhemoglobin171,215 and oxy-myoglobin,216 also react quite fast with peroxynitrite. 2.3.1. Heme Peroxidases and Heme Thiolate Proteins. The understanding of peroxynitrous acid reacting with heme peroxidases is far from complete. According to Uniprot (www. uniprot.org), there are six proteins belonging to the XPO subfamily of human peroxidases (Entries P11678, P22079, P05164, P07202, A1KZ92, and Q92626), but only myeloperoxidase (P05164) and lactoperoxidase (P22079) have been characterized in their reaction with peroxynitrite.183,217,218 The reactions of peroxynitrite with eosinophil peroxidase (P11678), thyroid peroxidase (P07202), and the recently described vascular peroxidases (VPO1 and VPO2, Q92626 and A1KZ92, respectively) have not been studied yet, despite their relative importance in specific cell types and tissues. Additional to XPO subfamily, the peroxidase-like domain of dual oxidases (Duox1 and Duox2) may bind heme and possess peroxidase activity,219 but their interaction with peroxynitrite has yet to be explored. Catalase reacts with peroxynitrous acid in a quite fast reaction220 contrary to the first report indicating no detectable reaction.183 Finally, of the two prostaglandin G/ H synthases, the reaction with the peroxidase domain of PGHS-1 has been described.221

theless, it has some drawbacks as there is not one single value for kapp[CO2] but a range that depends on the physical chemical conditions of the compartment where the reaction takes place. As shown by Lymar and Hurst,178 the reaction occurs strictly between ONOO− and CO2, and both have acid base equilibria that affect their availability at neutral pH. The dependence of the apparent reaction rate with proton concentration is given by eq 16. ⎛ ⎞⎛ ⎞ K aONOOH [H+] ⎟ ⎜ ⎟ kapp = k ⎜ ONOOH + [H+] ⎠⎝ K aCO2 + [H+] ⎠ ⎝ Ka

(16)

where k is the pH-independent rate constant that has values of 3 × 104 M−1 s−1 (25 °C)178 or 5.8 × 104 M−1 s−1 (37 °C);203 KaONOOH is the ionization constant of peroxynitrous acid (1.58 × 10−7),8 and KaCO2 is the apparent ionization constant of carbon dioxide (9.58 × 10−7).210 The pH dependence of kapp for the reaction of ONOO− with CO2 can thus be calculated at any desired pHs. Calculation of [CO2] is somewhat harder, as a first approach we could assume that CO2 is in equilibrium with bicarbonate, an equilibrium that can be reached either by reaction with hydroxide:211 CO2 + OH− → HCO3−

k = 8.5 × 104 (KW /[H+])

(17)

Or may proceed by hydration-ionization: CO2 + H 2O ⇌ H 2CO3

k f = 0.03 s−1; k r = 20 s−1

H 2CO3 ⇌ H+ + HCO3−(fast)

K a = 5.7 × 10−4

(18) (19) 1348


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Table 1. Reactions of Metal Proteins with Peroxynitrite rate constant with peroxynitrite metal enzyme horseradish peroxidase prostaglandin endoperoxide H syntase −1 myeloperoxidase lactoperoxidase chloroperoxidase catalase M. tuberculosis KatG S. typhimurium KatG endothelial nitric oxide synthase endothelial nitric oxide synthase (oxidase domain) inducible nitric oxide synthase neuronal nitric oxide synthase Bacillus subtilis nitric oxide synthase cytochrome P450 (BM-3) Campilobacter jejuni trHemoglobin P (FeIII) cystathionine β synthase cytochrome c Fe(II) oxyhemoglobin methemoglobin oxymyoglobin metmyoglobin aconitase MnSOD FeSOD Cu,Zn-SOD

kapp (M−1 s−1)

conditions

heme product

ref

3.2 × 10 1.02 × 106 1.7 × 107 2 × 107 6.8 × 106 3.3 × 105 1.96 × 106 1.7 × 106 1.4 × 105 4.2 × 104 7.5 × 105 2.7 × 106 2.1 × 105 2.3 × 105 1.3 × 105 1.0 × 106 4.1 × 106 5 × 104 1.3 × 104 2.4 × 104 3.9 × 104 5.4 × 104 7.7 × 104 1.4 × 105 1.3 × 105 4.3−4.6 × 104 1.88 × 104

25 °C, pH indep. 25 °C, pH 7.4 8 °C, pH 7 12 °C, pH indep. 25 °C, pH 7.4 12 °C, pH 7.4 23 °C, pH 5.1 23 °C, pH 7.1 37 °C, pH 7.4 25 °C, pH 7.4 37 °C, pH 7.4 37 °C, pH 7.4 20 °C, pH 7.4 20 °C, pH 7.4 20 °C, pH 7.4 12 °C, pH 6.8 25 °C, pH indep. 37 °C, pH 7.4 25 °C, pH 7.4 37 °C, pH 7.4 20 °C, pH 7.0 20 °C, pH 7.3 20 °C, pH 7.0 25 °C, pH 7.6 37 °C, pH 7.47 37 °C, pH 7.4 37 °C, pH = 7.53

compound I

183 225 221 183,217

6

compound I compound II compound II compound II compound I

183,218 223 220 226 227 224,228

compound I Fe(III)

229 230 231 193 171 232 216 232 185 78 81 233

Fe(III) Fe(III) Fe(III)

protein, including a decrease in Vmax and increase in Km and afterward irreversible loss of electron transfer activity for the catalyzed reduction of O2 to water.234,235 The functional and structural changes in the enzyme observed under a large excess of peroxynitrite are unlikely to be of any biological relevance. With regard to the catalytic activity of peroxynitrite reduction by cytochrome c oxidase at the expense of reducing equivalents provided by the electron transport chain (i.e., by cytochrome c2+), it has been correctly pointed out that the second-order rate constant with peroxynitrite is about two-orders of magnitude lower than that governing the reaction between the enzyme and O2.235 Thus, under physiological conditions oxygen is expected to typically outcompete peroxynitrite for the reaction with reduced cytochrome c oxidase. Also, under excess • NO (which binds and inhibits the enzyme with at least one order of magnitude higher affinity than O2), the cytochrome c oxidase-nitrosyl complex is not competent for peroxynitrite reduction.238 Still, under conditions of enhanced mitochondrial fluxes of peroxynitrite, cytochrome c oxidase may partially attenuate mitochondrial oxidative damage via peroxynitrite reduction to nitrite, including the reported inhibition of the tyrosine nitration of cytochrome c.235,239 Overall, under biologically relevant conditions cytochrome c oxidase may contribute, together with other enzymatic systems such as thiol peroxidases, to the mitochondrial reduction of peroxynitrite in the inner membrane region. 2.3.3. Iron−Sulfur Cluster Proteins. Peroxynitrite can readily react with some iron−sulfur-containing proteins; in particular, the peroxynitrite-sensitive ones are the group of dehydratases that have cubane [4Fe-4S] clusters in which one of the iron atoms (Feα) is not coordinated by polypeptide

A few heme-thiolate proteins have been studied in their reaction with peroxynitrite, most notably prostacyclin synthase,222 chloroperoxidase,223 and the oxygenase domain of nitric oxide synthase.224 Table 1 presents a summary of reaction rate constants of peroxynitrite with metal proteins. Overall it can be seen that hemeperoxidases and heme-thiolate proteins containing pentacoordinated iron tend to have larger rate constants in the 105−107 M−1 s−1 range, whereas hemeproteins containing hexacoordinated iron and nonheme metal proteins have smaller values. To complete the question of competitiveness, the concentration factor has to be considered, and that is a complex problem. Some metal proteins would be extremely concentrated in specialized cell types or subcellular compartments where they may become competitive targets in the consumption of peroxynitrite. 2.3.2. Cytochrome c Oxidase. Peroxynitrite reacts with the reduced form of cytochrome c oxidase at the binuclear heme a3-CuB site in a two-electron redox process to mainly yield nitrite (and some amounts of •NO) with a rate constant ≥106 M−1 s−1 at room temperature and physiological pH.234,235 At low and moderate concentrations of peroxynitrite, cytochrome c oxidase readily decomposes peroxynitrite and this process has been invoked to support the observation of the resistance of mitochondrial complex IV to peroxynitritemediated inactivation in isolated mitochondria and cells.190,236,237 However, in vitro experiments with purified cytochrome oxidase preparations at high peroxynitrite to cytochrome c oxidase ratio (>100:1) promote changes and oxidative processes in the protein, including heme degradation, which overall cause spectral and functional changes in the 1349


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nitration of Y151 and Y472, overoxidation of C126 and C385 and also S-glutathionylation of aconitase. Still, in spite of these possible oxidative posttranslational modifications, the main cause of aconitase inactivation is the reaction of peroxynitrite at the Feα of the active site iron−sulfur cluster. In contrast to the sensitivity of the labile [4Fe-4S] clusters to peroxynitrite, electron transfer enzymes that utilize iron−sulfur clusters with Fe atoms fully coordinated to the polypeptide chain are resistant to peroxynitrite. Indeed, [4Fe-4S], [3Fe-4S], and [2Fe-2S]-containing bacterial and mamamalian succinate dehydrogenase and NADH dehydrogenase are, in general, resistant to peroxynitrite,256,257 despite becoming nitrated in tyrosine residues. However, in the case of succinate dehydrogenase, it may become labile to peroxynitrite once the enzyme is depleted or affected at its accessory subunits that shield the clusters.258 Indeed, these additional mechanisms may serve to explain why peroxynitrite in excess affects succinate dehydrogenase activity and complex II-dependent respiration.190,236 In any case, when considering the sensitivity of iron−sulfur-containing mitochondrial enzymes to peroxynitrite, it is clear that m-aconitase is the premier target and this results in an important effect in energy metabolism due to its role in the metabolic control of the Krebs cycle.259

cysteine residues but only ligated to inorganic sulfurs of the cluster, leaving a free coordination position. This particular arrangement permits the Feα to bind a hydroxyl leaving group of the substrate to be dehydrated. The absence of a fourth cysteine ligand and an overall positive charge (2+) of the cluster makes it accessible and vulnerable to anionic oneelectron oxidants such as peroxynitrite (eq 20). Indeed,

mammalian mitochondrial and cytosolic (IRP1) aconitases,185,240 bacterial aconitase, 6-phosphogluconate dehydratase, and fumarase A241,242 are selective and early targets of peroxynitrite in vitro and in vivo. These enzymes have been also previously shown to be exquisitely sensitive to O2•−, with rate constants ca. 107 M−1 s−1.241 The reaction of O2•− and peroxynitrite with this type of iron−sulfur cluster leads to the release of the labile iron (Feα), the disruption of the cluster to [3Fe-4S] state and enzyme inactivation. Aconitases catalyze the reversible isomerization of citrate and isocitrate via cis-aconitate in the Krebs cycle. The second-order rate constant of the reaction for the mitochondrial enzyme with peroxynitrite was determined as 1.4 × 105 M−1 s−1 at pH 7.6 and 25 °C.185,243 The resulting inactive enzyme could be reactivated by reincorporation of Fe(II) to the 3Fe-4S cluster under appropriate reducing conditions in vitro and in vivo.185,242 On the other hand, •NO turned out to be a poor reactant and inactivator of m-aconitase, unless sustained levels over time were present.244 Overall, the experiments reporting the reactivity of peroxynitrite with m-aconitase185 helped to rationalize previous data on the effect of •NO synthesis or exposure in different cell types, resulting in an early loss of maconitase activity.245−249 Indeed, most of the •NO-dependent inactivation of cellular aconitases is now known to be mediated by peroxynitrite. The early reports with isolated aconitase preparations185,241 were key to expand the understanding of the cellular toxicity of •NO in terms of the participation of peroxynitrite and other •NO-derived oxidants. Later work also indicated that peroxynitrite was able to disrupt the iron−sulfur cluster of mammalian cytosolic aconitase240 (c-aconitase), also known as iron regulatory protein 1 (IRP1). The cluster-free protein (apo-IRP1) participates in the regulation of the expression of genes involved in iron metabolism. Activity, resonance Raman spectra and EPR data on human recombinant holo-IRP1 (rhIRP1) are consistent with the conversion of the [4Fe-4S]2+ to a [3Fe4S]1+ center upon exposure to peroxynitrite.250,251 Thus, peroxynitrite reactions with bacterial and mammalian aconitases lead to enzyme inactivation,185,241 iron release,242 and can also influence iron-regulatory pathways.240,251 Peroxynitrite can also cause m-aconitase tyrosine nitration in vitro243,252,253 and in vivo254,255 through the reactions of its secondary radicals; however, the generation of NO2Tyr in aconitase is not related to enzyme inactivation.243 For example, while substrates such as citrate protect m-aconitase from peroxynitrite-mediated inactivation, they do not modify the extent of enzyme nitration. Peptide mapping and mass spectrometry analysis have shown that peroxynitrite can cause

2.4. Reduction of Peroxynitrite by Thiols and Selenols

Thiols were among the first biological targets of peroxynitrite that were described.8 The reaction is a two-electron exchange with an SN2 mechanism in which the thiolate attacks peroxynitrous acid producing nitrite and the corresponding sulfenic acid (eq 21).260 The pH profiles of the apparent rate constants are described by eq 22 and are bell-shaped (Figure 3). RS− + ONOOH → RSOH + NO2−

(21)

⎞ ⎛ ⎞⎛ K aSH [H+] app ⎟ ⎜ ⎟ k pH = k RS−⎜ ONOOH + [H+] ⎠⎝ K aSH + [H+] ⎠ ⎝ Ka

(22)

The reaction of peroxynitrite with low molecular weight thiols differing in pKa reveals that the pH-independent rate

Figure 3. Simulated pH profiles of the apparent rate constants of several thiols reacting with peroxynitrite at 37 °C based in experimental data8,260 and using eq 22. The curves represent data generated for cysteine ethyl ester (black), cysteine (red), glutathione (blue), and dihydrolipoic acid (green). The vertical line marks pH 7.4 where most of the experimental determinations are made. 1350


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Table 2. Rate Constants of Peroxynitrite Reduction by Thiol-Containing Proteins protein Homo sapiens PRDX5

267,275

Xylella fastidiosa Ohr273 Mycobacterium tuberculosis AhpE285 Trypanosoma cruzi mTXNPx286 Mycobacterium tuberculosis TPx287 Plamodium falciparum AOP288 Homo sapiens PRDX2289,290 Arenicola marina Prx6291 Mycobacterium tuberculosis AhpC68 Mycobacterium tuberculosis PrxQ B292 Populus trichocarpa GPx 5272 Salmonella tiphymurium AhpC68 Helicobacter pylori AhpC68 Xylella fastidiosa PrxQ293 Trypanosoma cruzi cTXNPx286,294 Saccharomyces cerevisiae Tsa1225 Saccharomyces cerevisiae Tsa2225 Rattus norvegicus Prx6295 Giardia intestinalis Prx1a296 Giardia intestinalis ΔPrx1b296 Homo sapiens CD45297 Homo sapiens LAR297 Homo sapiens PTP1B297 Homo sapiens creatine kinase298,299 Homo sapiens DJ1300,301 Homo sapiens PDI302 Oryctolagus cuniculus GAPDH303,304 Homo sapiens arylamine N-acetyl transferase 1305 Homo sapiens tryptophan hydroxylase306 Mycobacterium tuberculosis Trx C307 Trypanosoma brucei TXN48,308 Bos taurus serum albumin8 Homo sapiens serum albuminc309,310 Pseudomonas aeruginosa DksA311 Pseudomonas aeruginosa DksA2311 cysteine (free amino acid)8 a

kappa (M−1 s−1) 7 × 10 1.2 × 108 2 × 107 1.9 × 107 1.8 × 107 1.5 × 107 1.5 × 107 1.4 × 107 2 × 106 1.51 × 106 1.4 × 106 1.4 × 106 1.33 × 106 1.21 × 106 1.04 × 106 1 × 106 7.4 × 105 5.1 × 105 3.7 × 105 4 × 105 2 × 105 2 × 108 2.3 × 107 2.2 × 107 8.85 × 105 2.7 × 105 6.9 × 104 6.25 × 104 5 × 104 3.4 × 104 1 × 104 ∼3.5 × 103 2.6 × 103 3.8 × 103 2.42 × 103 1.43 × 103 4.5 × 103 7

conditions pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH pH

7.8, 25 °C 7.4, 25 °C 7.4, 25 °C 7.4, 25 °C 7.4, 25 °C 7.4, 25 °C 7.4, 25 °C 7.4, 25 °C 7.4, 25 °C 6.75, RT 7.4, 25 °C 7.4, 25 °C 6.75, RT 6.75, RT 7.4, 37 °C 7.4, 25 °C 7.4, 25 °C 7.4, 25 °C 7.4, 25 °C 7, 4 °C 7, 4 °C 7.4, 37 °C 7.4, 37 °C 7.4, 37 °C 6.9, 37 °C 7.4, 25 °C 7.4, 25 °C 7.4, 25 °C 7.5, 37 °C 7.4, 25 °C 7.4, 25 °C 7.4, 25 °C 7.4, 37 °C 7.4, 37 °C 7.4, 25 °C 7.4, 25 °C 7.4, 37 °C

thiol pKa 5.2 NDd 5.2 NDd NDd NDd 5−6 5.1 one NO2Tyr/10,000 Tyr, under basal conditions; levels increase at least 1 order of magnitude under inflammatory conditions). However, this modification is favored in specific proteins, and, within proteins, in specific tyrosine residues and can cause structural and/or functional changes that are biologically relevant. For example, the nitration of Tyr34 in human MnSOD causes its inactivation in vitro and in vivo, and the sitespecificity in this case is explained by the Mn-catalyzed nitration reaction at the active site Tyr34; this modification provides a highly specific indication of peroxynitrite as the proximal •NOderived oxidant. In other cases, protein tyrosine nitration causes a gain-of-function, in some cases related to toxic activities. Thus, the formation of NO2Tyr constitutes not only a footprint of peroxynitrite but also in some cases can participate in its biological effects. In spite of a significant amount of literature, some aspects that require more precise definition are how peroxynitrite and protein tyrosine nitration participate in signal transduction cascades, how nitrated proteins are repaired and degraded, and how oxidative changes in biomolecules produced by peroxynitrite really translate to changes in function with quantitative and structural support. Recent work indicates that tyrosine and tryptophan nitration can be also catalyzed enzymatically, discoveries that expand the field of protein nitration biochemistry. In summary, peroxynitrite formation and protein tyrosine nitration are continuous events that occur in many organisms under physiological and pathological conditions; their role in human physiology, pathology, and aging has been largely established. There is plenty of room to use the biochemical knowledge obtained through over 25 years of research in these aspects of redox and free radical biochemistry in the translation into rational applications to the medical field.

could still help in defining the structural features of a given section of a protein. Some of these techniques include nuclear magnetic resonance (NMR), resonance Raman, and circular dichroism (CD). Given the particular spectroscopic characteristics in the visible range of NO2Tyr, resonance Raman represents a good way for detecting nitrated tyrosine residues in proteins.11 Furthermore, it can be used to obtain some information on the microenvironment of the nitrated residue, as well as to identify the protonation state of the nitrotyrosyl residue. For proteins containing chromophore prosthetic groups, like heme proteins, resonance Raman can also give structural information about that section of the protein, so it can be applied to study how its structure and interactions are affected by the nitration of tyrosine residues of the protein.807 The combination of resonance Raman with paramagnetic NMR was used to define the already mentioned structural changes induced in cytochrome c after nitration of solvent exposed Tyr74 and how such conformational change is coupled with the deprotonation of the nitrated tyrosine residue.688,689 The structural alterations induced by nitration of tyrosine residue 103 in myoglobin were studied also by a combination of spectroscopic techniques, including NMR and CD.808 Through the NMR approach, it was noted that nitrated Mb has a very similar overall tertiary structure than its native form but with a slightly more open conformation at the heme pocket with weaker iron-ligand interactions. At the secondary structure level, CD studies revealed that the α-helix content of nitrated Mb was slightly higher than for native Mb.808 For peroxynitritetreated LDL, in which apoB-100 contains several NO2Tyr residues, CD analysis indicated that nitrated apoB-100 contained a considerably lower content of α-helix than its native form, while it showed a greater content of β-sheet and random coil structure. These observations suggested that tyrosine nitration of apoB-100 by peroxynitrite, along with other nitrooxidative modifications, promoted the partial unfolding of the protein, as the major structural consequence of peroxynitrite promoted nitration and oxidation.809 The impact of tyrosine nitration on the secondary structure of αsynuclein was also analyzed by CD spectroscopy, in order to understand the effect of α-synuclein nitration on its aggregation events. Far-UV CD spectra showed that, after nitration of its four tyrosine residues, there was an increase on the ordered secondary structure content (mainly β-sheet) of α-synuclein in comparison with the natively unfolded monomer.810 These examples indicate that, independently of the elucidation of the three-dimensional structure of a nitrated protein or the development of computational simulations, several spectroscopic techniques, especially when used in combination, can provide information about the structural consequences of protein tyrosine nitration.

5. CONCLUSIONS AND PERSPECTIVES The occurrence of peroxynitrite in biological systems and its role as a potent and short-lived oxidant was originally proposed based on mechanistic and kinetic terms and later confirmed experimentally by detection of oxidative modifications in biomolecules (i.e., thiol oxidation, protein tyrosine nitration, and lipid peroxidation) and, more recently, via detection with chemical probes (e.g., with boronates); pharmacological and genetic-engineering approaches have been instrumental for unambiguously inferring the role of peroxynitrite in biological outcomes, including its participation as culprit in different 1385


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AUTHOR INFORMATION

Sebastián Carballal received his Ph.D. (2011, in Chemistry) at the Universidad de la República, Uruguay. Currently, he is Associate Professor of Biochemistry at the Facultad de Medicina, Universidad de República, Uruguay, and also a researcher at the Center for Free Radical and Biomedical Research, Universidad de la República, Uruguay. His research interests have focused in the field of proteins and the biochemistry of free radicals and redox processes. He has experience in a variety of biochemical procedures (protein purification, enzyme kinetics, bioanalytical methods) and in specialized techniques such as rapid kinetics approaches (stopped-flow spectroscopy). His current research is focused on the characterization of synthetic molecules with antioxidant capacity and evaluation of their cytoprotective effects during cellular challenge to nitro-oxidative stress conditions.

Corresponding Author

*Address: Departamento de Bioquı ́mica, Facultad de Medicina, Universidad de la República, Avda. General Flores 2125, 11800 Montevideo, Uruguay. E-mail: [email protected]. Tel: +598 2924 9561. ORCID

Rafael Radi: 0000-0002-1114-1875 Present Address @

N.R.: Cell Analysis Division, Agilent Technologies, Lexington, MA, United States.

Author Contributions ⊥

Natalia Romero obtained her Ph.D. in Chemistry in May 2007 working at the Department of Biochemistry, Facultad de Medicina, Universidad de la República, Uruguay. She was a postdoctoral fellow at the Brigham and Women’s Hospital−Harvard Medical School, USA, working with Dr. Thomas Michel. She has been Assistant Professor at the Department of Biochemistry, Facultad de Medicina, Universidad de la República, Uruguay, and investigator at the Center for Free Radical and Biomedical Research, Universidad de la República, Uruguay. Since 2015, she has been working as a Scientist at the Cell Analysis Division of Agilent Technologies, USA. Her research is focused on the study of reactivity and diffusional properties of reactive oxygen and nitrogen species and their role in signaling process and disease states.

G.F.-S. and N.C. contributed equally to this work.

Notes

The authors declare no competing financial interest. Biographies Gerardo Ferrer-Sueta obtained his M.Sc. in Inorganic Chemistry (UNAM, México, 1995) and his Ph.D. in Chemistry (Universidad de la República, Uruguay, 2006). He is currently an Assistant Professor of Biological Physical Chemistry at the School of Sciences, Universidad de la República. His research interests are focused on kinetics and mechanisms of redox reactions involving peroxides and thioldependent redox enzymes. He is a member of the Center for Free Radical and Biomedical Research.

Beatriz Alvarez received her M.Sc. (1993) and Ph.D. (1999) degrees in Chemistry from the Universidad de la República, Montevideo, Uruguay. She is now Associate Professor of Enzymology at the School of Sciences, Universidad de la República. She is also an investigator at the Center for Free Radical and Biomedical Research. Her research interests span the areas of redox biochemistry, kinetics, and enzymology, especially in relation to biological thiols and hydrogen sulfide.

Nicolás Campolo received his B.Sc. in Biochemistry in 2014 from the School of Sciences of the Universidad de la República, Uruguay. Since then, he has been a Ph.D. student in Biological Sciences, performing his work at the Department of Biochemistry at the School of Medicine and Center for Free Radical and Biomedical Research, Universidad de la Repúbica, Uruguay. His research focuses on the formation and biological consequences of the oxidative modifications in proteins, with a special focus on 3-nitrotyrosine and its derivatives. More specifically, he is now studying the mechanisms of the oxidative inactivation of human glutamine synthetase and its relation with pathological processes.

Rafael Radi received his M.D. (1988) and Ph.D. (1991, in Biochemistry) at the Universidad de la República, Montevideo, Uruguay. He was a postdoctoral fellow at the University of Alabama at Birmingham, USA, working with Bruce A. Freeman and Joseph S. Beckman, where he generated his first works of the biochemistry of peroxynitrite. He has been tenured faculty at the Department of Biochemistry, Facultad de Medicina, Universidad de la República, Uruguay, for three decades and is now its Professor and Chairman. He is the Director of the Center for Free Radical and Biomedical Research at the same University. Radi is a foreign member of the U.S. National Academy of Sciences and Howard Hughes Medical Institute alumni. His research interests have focused in the biochemistry of free radical and redox processes in oxidative stress and signaling, mitochondrial dysfunction, and oxidative post-translational modifications of proteins, including protein tyrosine nitration. He has applied rapid kinetic techniques, bioanalytical and immunochemical methods, electron paramagnetic resonance studies, and structural biology approaches to unravel the molecular basis of oxidative processes in disease states and characterize and evaluate redox-based therapeutics.

Madia Trujillo received her M.D. (1995) and Ph.D. in Biochemistry (2005) from Universidad de la República, Uruguay. She has been a faculty member of the Department of Biochemistry, Facultad de Medicina, Universidad de la República since 1991, where she is now an Associate Professor. She is a member of the Center for Free Radical and Biomedical Research, in Universidad de la República, Uruguay, where she leads a research line on enzymatic antioxidant systems. Particularly, she is interested in the functional and structural characterization of antioxidant systems of pathogenic microorganisms as well as human host cells. For that purpose, she applies a combination of rapid kinetic spectroscopy, electron paramagnetic resonance, as well as biophysical and biochemical analytic methods. Silvina Bartesaghi obtained her degree in Biochemistry in 2004 at the School of Sciences, Universidad de la República, and her Ph.D. in Chemistry at the School of Chemistry in 2010. Her research is focused on peroxynitrite-mediated posttranslational modifications and has worked during the last years in the mechanisms of tyrosine nitration/ oxidation in membranes. At the moment, she is studying the molecular basis of the oxidative inactivation of glutamine synthetase. Currently, she is an Associate Professor in Facultad de Medicina and investigator at the Center for Free Radical and Biomedical Research, Universidad de la República, Uruguay. She is also a Level I Investigator in the National Research System.

ACKNOWLEDGMENTS The authors are grateful to Dr. Valeria Valez for assistance with the artwork. Financial support was provided by the Universidad de la República (CSIC and Espacio Interdisciplinario, UdelaR), Agencia Nacional de Investigació n e Innovació n (FCE_2014_104233). Additional support was obtained from 1386


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Programa de Desarrollo de Ciencias Básicas (PEDECIBA), Centro de Biologı ́a Estructural del Mercosur (CeBEM), Centro Argentino Brasileño de Biotecnologı ́a (CABBIO), and Ridaline through Fundación Manuel Pérez (Facultad de Medicina, Universidad de la República). N.C. was partially supported by a fellowship from Universidad de la República (CAP_Uruguay), respectively. R.R. wishes to thank all the national and international collaborators that have jointly contributed to the topics presented in this review over the last 25 years.

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