Protein Tyrosine Nitration: Biochemical Mechanisms and Structural Basis of Functional Effects

Radí, Rafael

doi:10.1021/ar300234c

Cited by 438 publications

(413 citation statements)

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“…Indeed, all of the secondary radicals arising from peroxynitrite ( ⅐ OH, CO 3 . , oxo-metal complexes, lipid peroxyl radicals (33), and ⅐ NO 2 ) promote protein tyrosine oxidation and nitration (41). The typical mechanism of tyrosine nitration in biological systems is a two-step radical process: a one-electron oxidant leading to the formation of a tyrosyl radical (Equation 10), which then combines at diffusion-controlled rates with ⅐ NO 2 to yield 3-nitrotyrosine (Equation 11) (42).…”

Section: Peroxynitrite-mediated Protein Tyrosine Nitrationmentioning

confidence: 99%

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Peroxynitrite, a Stealthy Biological Oxidant

Radí

2013

Journal of Biological Chemistry

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714

444

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Peroxynitrite is the product of the diffusion-controlled reaction of nitric oxide and superoxide radicals. Peroxynitrite, a reactive short-lived peroxide with a pK a of 6.8, is a good oxidant and nucleophile. It also yields secondary free radical intermediates such as nitrogen dioxide and carbonate radicals. Much of nitric oxide-and superoxide-dependent cytotoxicity resides on peroxynitrite, which affects mitochondrial function and triggers cell death via oxidation and nitration reactions. Peroxynitrite is an endogenous toxicant but is also a cytotoxic effector against invading pathogens. The biological chemistry of peroxynitrite is modulated by endogenous antioxidant mechanisms and neutralized by synthetic compounds with peroxynitrite-scavenging capacity.

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Section: Peroxynitrite-mediated Protein Tyrosine Nitrationmentioning

confidence: 99%

“…proteins (41); in this case, the metal promotes the initial oneelectron oxidation and enhances nitration yields in vicinal tyrosine residues (e.g. in Mn-SOD; see below) (43).…”

mentioning

confidence: 99%

Peroxynitrite, a Stealthy Biological Oxidant

Radí

2013

Journal of Biological Chemistry

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714

444

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“…The determinants of this selectivity are not fully established yet, but some relevant factors have been identified, like the protein structure, the nitration mechanism, and the environment where the protein is located. 24,29 A particular case where the selectivity of tyrosine nitration seems more clear is in transition metal-containing proteins that have tyrosine residues close to the metal center. Two well-described examples of this are the MnSOD and the prostacyclin synthase, where a particular tyrosine residue is nitrated by ONOO − .…”

Section: Site-specificity In Transition Metal-catalyzed Protein Tyrosmentioning

confidence: 99%

Metal-catalyzed protein tyrosine nitration in biological systems

Campolo¹,

Bartesaghi

Radí

2014

Redox Report

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Protein tyrosine nitration is an oxidative postranslational modification that can affect protein structure and function. It is mediated in vivo by the production of nitric oxide-derived reactive nitrogen species (RNS), including peroxynitrite (ONOO − ) and nitrogen dioxide ( • NO 2 ). Redox-active transition metals such as iron (Fe), copper (Cu), and manganese (Mn) can actively participate in the processes of tyrosine nitration in biological systems, as they catalyze the production of both reactive oxygen species and RNS, enhance nitration yields and provide site-specificity to this process. Early after the discovery that protein tyrosine nitration can occur under biologically relevant conditions, it was shown that some low molecular weight transition-metal centers and metalloproteins could promote peroxynitrite-dependent nitration. Later studies showed that nitration could be achieved by peroxynitrite-independent routes as well, depending on the transition metal-catalyzed oxidation of nitrite (NO 2 − ) to • NO 2 in the presence of hydrogen peroxide. Processes like these can be achieved either by hemeperoxidase-dependent reactions or by ferrous and cuprous ions through Fenton-type chemistry. Besides the in vitro evidence, there are now several in vivo studies that support the close relationship between transition metal levels and protein tyrosine nitration. So, the contribution of transition metals to the levels of tyrosine nitrated proteins observed under basal conditions and, specially, in disease states related with high levels of these metal ions, seems to be quite clear. Altogether, current evidence unambiguously supports a central role of transition metals in determining the extent and selectivity of protein tyrosine nitration mediated both by peroxynitritedependent and independent mechanisms.

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“…• , which are apparently limited to 3-nitro-tyrosine and 3,3'-dityrosine, 61,62 despite the considerable spin density of the Tyr…”

Section: On the Structure Of Trp-trp Cross-links Produced By Radical mentioning

confidence: 99%

Ditryptophan Cross-Links as Novel Products of Protein Oxidation

Paviani

Galdino

Prazeres

et al. 2017

J. Braz. Chem. Soc.

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Protein oxidation is an unavoidable consequence of aerobic metabolism. The oxidation of most proteins residues is non-repairable and may affect protein structure and function. In particular, protein cross-links arising from oxidative modifications are presumably toxic to cells because they may accumulate and induce protein aggregation. However, most of these irreversible protein cross-links remain partially characterized. Up to very recently, ditryptophan cross-links (Trp-Trp), in particular, have been largely disregarded in the literature. Here, we briefly review studies showing that Trp-Trp cross-links can be formed in proteins exposed to a variety of oxidants. The challenges to fully characterize Trp-Trp cross-links are discussed as well as their potential roles in protein dysfunction and aggregation.Keywords: ditryptophan, cross-links, protein oxidation, free radicals Protein OxidationFree radicals and other oxidants are formed in living organisms by oxidation-reduction processes, which occur continuously during metabolism and through interactions with the environment. Organisms evolved enzymatic antioxidant defenses and the capability to use antioxidants from the diet to control the levels of these species. 1,2 Nevertheless, under certain circumstances, the levels of radicals and oxidants increase, promoting the oxidation of biomolecules. Among them, proteins are the major targets, due to their high biological abundance and reactivity towards one-and two-electron oxidants. [3][4][5] Protein residues most susceptible to oxidation are the sulfur-containing residues Cys and Met, and the aromatic residues His, Phe, Tyr, and Trp. In vivo, the oxidation of Cys and Met residues can be reversed by biological reductants with the assistance of enzymatic systems. In fact, the reversible oxidation of protein-Cys residues is emerging as a fundamental cell regulatory mechanism. 2,[6][7][8] The oxidation of all the other protein residues is irreversible, and includes several covalent modifications, such as protein cleavage, carbonylation, nitration, hydroxylation, halogenation and protein cross-linking with other proteins, lipids, carbohydrates and nucleic acids. [3][4][5][9][10][11] These modifications result in protein fragmentation, loss of protein function, protein aggregation and/or altered protein turnover, leading to cell and tissue dysfunction and various human pathologies. To maintain cellular homeostasis, proteins irreversibly oxidized are targeted for degradation by the proteasomal and lysosomal degradation pathways.11,12 During aging and pathological conditions associated with oxidative stress, however, the levels of over-oxidized and cross-linked proteins accumulate because these species are poor substrates for the intracellular proteolytic systems. This may lead to protein aggregation, which is a hallmark of age-related diseases, such as neurodegenerative diseases, atherosclerosis and cataract.11,12 Therefore, the study of irreversible protein oxidation in vitro and in vivo is relevant to the understanding o...

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Protein Tyrosine Nitration: Biochemical Mechanisms and Structural Basis of Functional Effects

Cited by 438 publications

References 39 publications

Peroxynitrite, a Stealthy Biological Oxidant

Peroxynitrite, a Stealthy Biological Oxidant

Metal-catalyzed protein tyrosine nitration in biological systems

Ditryptophan Cross-Links as Novel Products of Protein Oxidation

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