Transmembrane Nitration of Hydrophobic Tyrosyl Peptides

Zhang, Hao; Bhargava, Kalpana; Keszler, Ágnes; Feix, Jimmy B.; Hogg, Neil; Joseph, Joy; Kalyanaraman, B.

doi:10.1074/jbc.m211561200

Cited by 54 publications

(14 citation statements)

References 53 publications

(77 reference statements)

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“…Our data are consistent with an earlier observation (26) that ONOO Ϫ and the NO 2 Ϫ /H 2 O 2 /MPO mixture nitrated many of the same protein bands in rat heart homogenate. This tempted us to support a conclusion (15,16) that a single nitrating species (presumably ⅐ NO 2 ) may be formed, which is common for both reactions. The conclusion is further supported by the notion that mitochondrial proteins from ALR mice were protected against nitration.…”

Section: Discussionmentioning

confidence: 94%

“…Because the local environment of the targeted tyrosine residue may also play a key role in determining the rate of nitration and eventually the final outcome of the reaction (16,25), mitochondrial soluble and mitochondrial membrane proteins were analyzed separately. The two-dimensional PAGE patterns of in vitro nitrated proteins were found remarkably similar for ONOO Ϫ -and MPO-dependent reactions in both soluble (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…A recent development points to the common nitrating species (nitrogen dioxide, ⅐ NO 2 ) formed from both pathways, which is responsible for the most nitrotyrosine generated (15,16). Despite some progress in assessing the putative mechanism of in vivo nitration, the biological relevance of protein tyrosine nitration remains unclear.…”

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confidence: 99%

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Protein Tyrosine Nitration in the Mitochondria from Diabetic Mouse Heart

Turko

Li²,

Aulak

et al. 2003

Journal of Biological Chemistry

214

152

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Oxidative stress has been implicated in dysfunctional mitochondria in diabetes. Tyrosine nitration of mitochondrial proteins was observed under conditions of oxidative stress. We hypothesize that nitration of mitochondrial proteins is a common mechanism by which oxidative stress causes dysfunctional mitochondria. The putative mechanism of nitration in a diabetic model of oxidative stress and functional changes of nitrated proteins were studied in this work. As a source of mitochondria, alloxan-susceptible and alloxan-resistant mice were used. These inbred strains are distinguished by the differential ability to detoxify free radicals. A proteomic approach revealed significant similarity between patterns of tyrosine-nitrated proteins generated in the heart mitochondria under different in vitro and in vivo conditions of oxidative stress. This observation points to a common nitrating species, which may derive from different nitrating pathways in vivo and may be responsible for the majority of nitrotyrosine formed. Functional studies show that protein nitration has an adverse effect on protein function and that protection against nitration protects functional properties of proteins. Because proteins that undergo nitration are involved in major mitochondrial functions, such as energy production, antioxidant defense, and apoptosis, we concluded that tyrosine nitration of mitochondrial proteins may lead to dysfunctional mitochondria in diabetes.Protein tyrosine nitration is a common post-translational modification occurring under conditions of oxidative stress in a number of diseases (1, 2). Diabetes is a state of oxidative stress (3, 4). The studies on diabetic mitochondria suggest that diabetes causes dysfunctional mitochondria (5-8). Furthermore, the studies that associate altered free radical status with impaired mitochondrial function provide evidence of protein tyrosine nitration in mitochondria exposed to oxidative stress (9 -13), including diabetic mitochondria (14). These observations may have important implications for the pathogenesis of diabetes if the protein targets of nitration, functional consequences of nitration, and pathways for the increase of protein tyrosine nitration in mitochondria were established.Over the past several years, substantial evidence has been accumulated that major pathways of protein tyrosine nitration in vivo include peroxynitrite (ONOO Ϫ ) and heme peroxidasedependent reactions (1). A recent development points to the common nitrating species (nitrogen dioxide, ⅐ NO 2 ) formed from both pathways, which is responsible for the most nitrotyrosine generated (15, 16). Despite some progress in assessing the putative mechanism of in vivo nitration, the biological relevance of protein tyrosine nitration remains unclear. Very little is known about which specific proteins undergo nitration and whether disease-associated nitration contributes to the appearance of complications or whether it is merely a biomarker, reflecting the presence of complications.Our hypothesis is that nitration of m...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protein Tyrosine Nitration in the Mitochondria from Diabetic Mouse Heart

Turko

Li²,

Aulak

et al. 2003

Journal of Biological Chemistry

214

152

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“…2S. The peptides were chemically synthesized using the standard Fmoc solid phase peptide-based synthetic procedure on an Advanced Chemtech model 90 synthesizer (Louisville, KY) (23). Rink amide methylbenzhydrylamine resin (loading 0.72 mmol/g) was used as a solid support.…”

Section: Peptide Synthesis and Purificationmentioning

confidence: 99%

“…Previously, we have shown, using membrane-incorporated tyrosine analogs and tyrosyl peptides, that dityrosine formation is not a significant reaction process for tyrosyl radicals in membranes due to hindrance of free diffusion of tyrosyl radicals (22). In addition, the location of the tyrosyl probe in the membrane determines the transmembrane nitration profile (23). Literature data show that the CO 2 levels greatly influence the kinetics of tyrosyl nitration in proteins (24,25).…”

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confidence: 99%

Intramolecular Electron Transfer between Tyrosyl Radical and Cysteine Residue Inhibits Tyrosine Nitration and Induces Thiyl Radical Formation in Model Peptides Treated with Myeloperoxidase, H2O2, and NO2-

Zhang

Joseph

et al. 2005

Journal of Biological Chemistry

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. However, increased tyrosine nitration, tyrosine dimerization, and tyrosyl radical formation were detected in the MPO/H 2 O 2 /NO 2 ؊ /YCSSCH 3 system. Increased formation of S-nitrosated YC (YCysNO) was detected in the MPO/H 2 O 2 / ⅐ NO system. We conclude that a rapid intramolecular electron transfer reaction between the tyrosyl radical and the Cys residue impedes tyrosine nitration and induces corresponding thiyl radical and nitrosocysteine product. Implications of this novel intramolecular electron transfer mechanism in protein nitration and nitrosation are discussed.There is increasing evidence for generation of inflammatory oxidants including the reactive oxygen/nitrogen species in the progression and pathogenesis of cardiovascular, pulmonary, and neurodegenerative diseases (1-9). Supporting evidence came from the identification of the post-translational modification of protein and lipid oxidation/nitration marker products (10 -12). Prominent nitrative, nitrosative, and oxidative reactions in tissues include tyrosine nitration, cysteine and tryptophan nitrosation, tyrosine, tryptophan, histidine, and methionine oxidation and lipid oxidation/nitration (12-15). The goal of the present study was to monitor the influence of a cysteine residue on tyrosine nitration. Several studies have shown that tyrosine nitration is a selective process that is controlled by various microenvironmental factors (hydrophobicity, CO 2 levels, membrane oxygen concentration, acidic environment, and amino acid sequence) (16 -21). Previously, we have shown, using membrane-incorporated tyrosine analogs and tyrosyl peptides, that dityrosine formation is not a significant reaction process for tyrosyl radicals in membranes due to hindrance of free diffusion of tyrosyl radicals (22). In addition, the location of the tyrosyl probe in the membrane determines the transmembrane nitration profile (23). Literature data show that the CO 2 levels greatly influence the kinetics of tyrosyl nitration in proteins (24,25).Factors influencing nitration of tyrosyl residues in protein are not fully known. As discussed in previous reviews (12,21,26), the local environment of tyrosine residues within the secondary and tertiary structure of the protein will probably influence the site of tyrosine nitration. Although no specific amino acid sequence criteria exist for predicting tyrosine nitration or lack thereof, it has been shown, as originally suggested, that protein tyrosyl nitration is (i) enhanced when tyrosine is situated closer to a negatively charged amino acid (i.e. glutamate or aspartate) and (ii) decreased when tyrosine residue is present in the vicinity of a cysteinyl or methionine residue (12,21,26). However, detailed quantitative analysis of these effects on tyrosyl nitration is lacking, although a more recent report focused on the effect of lysine residues on tyrosyl nitration (27). Understanding the biophysical/biochemical mechanisms that determine the motif for nitration-sensitive tyrosine residues has physiological and pathophysiological ...

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