Nitric oxide, oxidants, and protein tyrosine nitration
The occurrence of protein tyrosine nitration under disease conditions is now firmly established and represents a shift from the signal transducing physiological actions of • NO to oxidative and potentially pathogenic pathways. Tyrosine nitration is mediated by reactive nitrogen species such as peroxynitrite anion (ONOO – ) and nitrogen dioxide ( • NO 2 ), formed as secondary products of • NO metabolism in the presence of oxidants including superoxide radicals ( \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{O}}_{2}^{{\bullet}-}\end{equation*}\end{document} ), hydrogen peroxide (H 2 O 2 ), and transition metal centers. The precise interplay between • NO and oxidants and the identification of the proximal intermediate(s) responsible for nitration in vivo have been under controversy. Despite the capacity of peroxynitrite to mediate tyrosine nitration in vitro , its role on nitration in vivo has been questioned, and alternative pathways, including the nitrite/H 2 O 2 /hemeperoxidase and transition metal-dependent mechanisms, have been proposed. A balanced analysis of existing evidence indicates that ( i ) different nitration pathways can contribute to tyrosine nitration in vivo , and ( ii ) most, if not all, nitration pathways involve free radical biochemistry with carbonate radicals ( \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{CO}}_{3}^{{\bullet}-}\end{equation*}\end{document} ) and/or oxo–metal complexes oxidizing tyrosine to tyrosyl radical followed by the diffusion-controlled reaction with • NO 2 to yield 3-nitrotyrosine. Although protein tyrosine nitration is a low-yield process in vivo , 3-nitrotyrosine has been revealed as a relevant biomarker of • NO-dependent oxidative stress; additionally, site-specific nitration focused on particular protein tyrosines may result in modification of function and promote a biological effect. Tissue distribution and quantitation of protein 3-nitrotyrosine, recognition of the predominant nitration pathways and individual identification of nitrated proteins in disease states open new avenues for the understanding and treatment of human pathologies.