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to the phenolic hydroxyl group) leading to protein tyrosine nitration (PTN) [5]. Protein tyrosine nitration exhibits a certain degree of selectivity and not all tyrosine residues are nitrated since nitration may rather depend on the residue’s accessibility to solvents. Neither the abundance of a protein nor the number of tyrosine residues in a given protein can help us predict whether it is a target for PTN [2,3,6]. For example, human serum albumin (HSA) is less extensively nitrated than other plasma proteins, although being the most abundant plasma protein [6]. While HSA has 18 tyrosine residues, an in vitro study of peroxynitrite-mediated PTN showed that only two tyrosine residues are particularly susceptible to nitration [7]. The reactivity of a tyrosine residue might also depend on the nature of the reactive species [2]. While peroxynitrite (ONOO - ) and tetranitromethane (TNM) nitrate certain proteins [8], there are differences in PTN patterns in other proteins [9-11]. The nitration of protein tyrosine residues could dramatically change protein structure and conformation and subsequently alter their function [12-15]. Tyrosine nitration sites are localized within specific functional domains of nitrated proteins [16]. For example, a strong inhibition of the catalytic activity of manganese-superoxide dismutase (MnSOD) by peroxynitrite-mediated PTN has been reported and explained by nitration of the essential tyrosine residue [17]. The inactivation of human MnSOD by peroxynitrite is caused by exclusive nitration of tyrosine 34 (Tyr34) to 3-nitrotyrosine [18]. Role of Free Radical Species in Tyrosine Nitration Nitrogen dioxide, nitrous acid, nitryl chloride, and certain peroxidases [19] derived from inflammatory cells can mediate the nitration of tyrosine to form 3-NT (Table 1). For example, nitrite (NO 2 -), a primary autoxidation product of NO [20], is further oxidized to form nitrogen dioxide by the action of peroxidases, e.g., myeloperoxidase and eosinophil peroxidase, heme proteins that are abundantly expressed in activated leukocytes. The resulting nitrogen dioxide nitrates the tyrosine residues in the presence of hydrogen peroxide (H 2 O 2 ) [21]. Therefore, tyrosine nitration is based on the generation of nitrogen dioxide radicals (NO 2 ) by various hemoperoxydases in the presence of H 2 O 2 and nitrite [22-24]. Other plausible reactions are based on (i) the interaction of nitric oxide with a tyrosyl radical, (ii) the direct action of nitrogen dioxide, (iii) the formation of nitrous acid by acidification of nitrite, (iv) the oxidation of nitrite by hypochlorous acid to form nitryl chloride (NO 2 Cl), (v) the action of acyl or alkyl nitrates or (vi) the action of metal nitrates [1,25,26]. Hence, nitrotyrosine is therefore likely not a footprint for peroxynitrite alone but more generally a marker of nitrative stress. Nitrating Agent Proteins nitrated References Hemoperoxidases (myeloperoxidase, MPO peroxidase) – MPO/H 2 O 2 system Nitrite (NO 2- ) Nitroprusside (nitropress) Peroxynitrite (ONO 2– ) Tetranitromethane (TNM) lipoproteins hemoglobin p65 (NF-κB) human serum albumin, creatine kinase, cytochrome c, hemoglobin, NADH dehydrogenase, succinate dehydrogenase, H2A histone protein bovine serum albumin, human serum albumin Table 1: Factors or agents that lead to the formation of tyrosine nitrated proteins. Tsikas (2012), Abello et al (2009). The reactive nitrogen species, peroxynitrite, is an important nitrating agent in vivo. However, it is not the only source of 3-NT formation in vivo. Initially, 3-NT was thought to be a biomarker of the existence of peroxynitrite, and protein tyrosine nitration was believed to be the biomarker of peroxynitrite formation in biological systems [27,28]. However, later studies demonstrated that some hemoproteins such as hemoglobin and myoglobin could catalyze NaNO 2 /H 2 O 2 -dependent nitration of tyrosine to yield 3-NT [29-31]. The possible underlying mechanism is that hemoproteins catalyze the oxidation of nitrite to nitrogen dioxide (NO 2 ) which reacts with tyrosine radical (Tyr . ) to form 3-NT [27,32,33]. Peroxynitrite and related reactive nitrogen species are capable of both oxidation and nitration of the aromatic side-chains of tyrosine and tryptophan in proteins [34,35], resulting in a condition known as “nitrosative stress”. Reactive oxygen species (ROS) and reactive nitrogen species (RNS)-mediated damage in the central nervous tissues may reflect an underlying neuroinflammatory process [36]. Protein damage that occurs under conditions of oxidative stress may represent direct oxidation of protein side-chains by ROS and/ or RNS or adduction of secondary products of oxidation of sugars (glycoxidation), or polyunsaturated fatty acids (lipid peroxidation) [36]. In addition to the well known or standard reactive oxygen and nitrogen species, oxidative damage to proteins can occur due to alternate oxidants (e.g., HOCl) and circulating oxidized amino acids such as tyrosine radical generated by metalloenzymes such as, myeloperoxidase [37]. The accumulation of oxidized protein is a complex function of the rates of ROS formation, antioxidant levels, and the ability to proteolytically eliminate ion of oxidized forms of proteins [38]. Carbon dioxide/bicarbonate (1.3 and 25 mM in plasma, respectively) [39] strongly influence peroxynitrite-mediated reactions [39- 43] and enhance nitration of aromatic rings as in tyrosine. They can also promote nitration in the presence of antioxidants (such as uric acid, ascorbate and thiols), which normally inhibit nitration, while partially inhibiting the oxidation of thiols. Carbon dioxide reacts with peroxynitrite to form the nitrosoperoxycarbonate anion (ONOOCO 2- ), which subsequently rearranges to form the nitrocarbonate anion (O 2 NOCO 2- ). The latter is considered to be the direct oxidant of peroxynitrite-mediated reagents in biological environments [43]. Peroxynitrite-mediated tyrosine nitration is also accelerated in the presence of transition metal ions, either in free form (Cu 2+ , Fe 3+ , Fe 2+ ) or as complexes involving protoporphyrin IX (heme) or certain chelators - ethylene diamine tetraacetic acid (EDTA) [15,16,44]. Hence, metal ions catalysis plays an important role in the nitration of protein residues in proteins [45]. Role of Protein Tyrosine Nitration in Pathological Conditions A variety of proteins are nitrated at tyrosine residues both in vitro and in vivo by the reaction with peroxynitrite (Table 2) [46-49]. These include, for instance, glutamine synthase [50], cdc2 kinase [51], bovine serum albumin (BSA) [52], MnSOD [53], phosphatidylinositol 3-kinase (PI3K) [54], and tyrosine hydroxylase [55]. A proteomic approach has been able to identify more than 40 NT-carrying proteins that become modified as a consequence of inflammatory responses [5]. The formation of 3-NT proteins has been detected histochemically in inflamed or infected tissues (Figures 2 and 3). Synovial fluid from patients with rheumatoid arthritis (RA) was found to contain a higher concentration of NT-carrying immunoglobulin G (IgG) as compared to osteoarthritic (OA) specimens [56,57]. Peroxynitrite reacts with several amino acids such as tyrosine, phenylalanine and histidine that are modified through intermediary secondary species OMICS Group eBooks 004
[58-61]. Protein sulfhydryls [62] and tyrosyl residues are the principal targets of peroxynitrite in proteins [63,64]. Nitration is maximal at physiological pH (pH 7.4), and its yield decreases under more acidic or basic conditions [64,65]. Protein Reactive nitrogen Species Pathological condition References ATP synthase complex I (FoF1 complex, F1-ATPase) Peroxynitrite inflammation, ischemia Creatine kinase Peroxynitrite myocardial infarction Cytochrome c Peroxynitrite inflammation, ischemia Glyceraldehy 3 phosphate dehydrogenase (GAPDH) Histone protein (H2A) Manganese superoxide dismutase (MnSOD) NADH dehydrogenase (NADH ubiquinone oxidoreductase, Complex I) Sarcoplasmic reticulum Ca 2+ ATPase (SERCA2, calcium pump 2) Peroxynitrite Peroxynitrite Peroxynitrite Peroxynitrite Peroxynitrite cardiovascular, neurological diseases systemic lupus erythematosus, rheumatoid arthritis neurodegenerative diseases ischemia reperfusion myocardial infarction Serum proteins Nitric oxide systemic lupus erythematosus Succinate dehydrogenase (complex II, succinate-coenzyme Q reductase) Peroxynitrite ischemia Synovial tissue proteins nitric oxide rheumatoid arthritis, osteoarthritis Tau protein Peroxynitrite Alzheimer’s disease Table 2: Role of protein tyrosine nitration in various pathological conditions. Souza et al (2008), Yeo et al (2008), Tsikas (2012), Peluffo and Radi (2007), Lee et al (2009) Figure 2: Immunohistochemistry of protein tyrosine nitration. The figure shows nitrotyrosine staining of a human lymph node undergoing nonspecific immune activation. The arrowheads indicate 3-nitrotyrosine immunoreactivity in macrophages (adapted from Radi et al, 2001). Figure 3: Arteries immunostained with anti-nitrotyrosine antibodies. (A) The nitrotyrosine immunostaining of arteries from a healthy donor (B) chronic kidney disease patient (adapted from Guilgen et al, 2011). Nitration of tyrosine residues can profoundly alter protein structure and function, suggesting that protein nitration may be fundamentally related to and predictive of oxidative cell injury. The subsequent release of altered proteins may enable them to act as antigens inducing antibodies against self-proteins. The biological significance of tyrosine nitration supports the formation of 3-NT in vivo in diverse pathologic conditions and 3-NT is thought to be a relatively specific marker of oxidative damage mediated by peroxynitrite and other nitrogen free radical species. The immunoreactivity of 3-NT has been reported in several human pathological conditions. Free/ protein-bound tyrosine are attacked by various RNS, including peroxynitrite, to form free/protein-bound 3-NT, which may provide insight into the mechanism of severe disease activity as seen in lupus patients [66]. In addition, numerous other disease states using nonhuman models have been shown to involve the formation of 3-NT [67]. Elevated levels of 3-nitrotyrosine have been reported is various human pathologies such as atherosclerosis, multiple sclerosis, OMICS Group eBooks 005
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