Protein tyrosine nitration in hydrophilic and hydrophobic environments

Abstract

In this review we address current concepts on the biological occurrence, levels and consequences of protein tyrosine nitration in biological systems. We focused on mechanistic aspects, emphasizing on the free radical mechanisms of protein 3-nitrotyrosine formation and critically analyzed the restrictions for obtaining large tyrosine nitration yields in vivo, mainly due to the presence of strong reducing systems (e.g. glutathione) that can potently inhibit at different levels the nitration process. Evidence is provided to show that the existence of metal-catalyzed processes, the assistance of nitric oxide-dependent nitration steps and the facilitation by hydrophobic environments, provide individually and/or in combination, feasible scenarios for nitration in complex biological milieux. Recent studies using hydrophobic tyrosine analogs and tyrosine-containing peptides have revealed that factors controlling nitration in hydrophobic environments such as biomembranes and lipoproteins can differ to those in aqueous compartments. In particular, exclusion of key soluble reductants from the lipid phase will more easily allow nitration and lipid-derived radicals are suggested as important mediators of the one-electron oxidation of tyrosine to tyrosyl radical in proteins associated to hydrophobic environments. Development and testing of hydrophilic and hydrophobic probes that can compete with endogenous constituents for the nitrating intermediates provide tools to unravel nitration mechanisms in vitro and in vivo; additionally, they could also serve to play cellular and tissue protective functions against the toxic effects of protein tyrosine nitration.

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Recently, it also became evident that a number of drugs, such as antiinflammatory drugs, statins, and antibiotics, which supposedly aimed at different targets in unlike disorders, have the regulation of oxidative stress as a prominent mode of action, thus potentiating the widespread awareness of the role that oxidative stress plays in several diseases and injuries (3,27,47,55,64,155,175,188,209,228,312,336). Superoxide dismutase is an endogenous and first-line-of-defense enzyme that eliminates superoxide by catalyzing its dismutation into O 2 and H 2 O 2 (119,120,212,240).…”

“…Whatever mechanism is in action, antioxidants would also decrease the levels of oxidatively modified biologic molecules. Reactive species, such as O 2 ·À , H 2 O 2 , and · NO, and oxidatively modified biologic molecules (e.g., nitrated lipids and nitrosated proteins) all appear to be involved in signaling events; their removal affects both primary oxidative damage and redox-based cellular transcriptional activity (27,47,55,188,273,298,312,336). Therefore, antioxidants influence both inflammatory and immune pathways and also modulate secondary oxidativestress processes.…”

“…Reactive species, such as nitric oxide ( · NO), superoxide (O 2 ·À ), hydrogen peroxide (H 2 O 2 ), peroxynitrite (ONOO -), and others have been widely recognized as signaling species that, by affecting redox-based cellular transcriptional activity, control inflammatory and immune responses and enhance secondary oxidative stress (27,47,96,151,188,273,276,298,335,336). Mitochondria, the major producers of reactive species, are consistently found to play a critical role in oxidative stress (55,155,228,312).…”

Short-term alpha- or gamma-delta-enriched tocopherol oil supplementation differentially affects the expression of proinflammatory mediators: selective impacts on characteristics of protein tyrosine nitration in vivo

“…Within the living biological matrix, this could be made more complex due to the distribution kinetics of the tocopherols in membrane structures and the physico-chemical relationships that dictate the relative accessibility of nitrating reagents to target tyrosines as well as tocopherols in hydrophobic and aqueous regions, lipid rafts and caveolae of membranes and biomolecules. [49][50][51] It must be remembered, however, that many cellular receptor-mediated and stress sensing functions can be localized to these membrane subdomains and that it is in these localities that many aspects of the cellular response to stress are integrated, particularly in structures harboring NO synthase. 6,52 Of course this is all dependent on the microenvironment in the cell and localized concentrations of the reactants.…”

Amino acid and protein modification by oxygen and nitrogen species

“…These include NO-derived reactions with proteins, which appear to have important functional consequences (Bartesaghi et al 2007;Souza et al 2008;Ischiropoulos 2009). In this special issue, two manuscripts have described biological and methodological aspects concerning the analysis of protein-bound 3 0 -nitrotyrosine.…”