Protein nitration is mediated by heme and free metals through Fenton-type chemistry: An alternative to the NO/O\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\setlength{\oddsidemargin}{-69pt}\begin{document}\begin{equation*}{\mathrm{_{2}^{-}}}\end{equation*}\end{document} reaction

Abstract

The chemical origins of nitrated tyrosine residues (NT) formed in proteins during a variety of pathophysiological conditions remain controversial. Although numerous studies have concluded that NT is a signature for peroxynitrite (ONOO ؊ ) formation, other works suggest the primary involvement of peroxidases. Because metal homeostasis is often disrupted in conditions bearing NT, the role of metals as catalysts for protein nitration was examined. nitrotyrosine ͉ nitric oxide ͉ peroxynitrite ͉ oxidation ͉ hemin N itrated tyrosine residues (NT) have been used as a marker of the involvement of nitric oxide (NO) and its related chemistry in a number of pathophysiological disorders including cardiovascular (1, 2) neurodegenerative and malignant conditions (1-5), such as septic shock (6), multiple sclerosis (7), Alzheimer's disease (8), and amyotrophic lateral sclerosis (9). In cancer the presence of NT often correlates with a poor prognosis (10), suggesting diagnostic implications.Several mechanisms for NT formation have been proposed, and its origin remains controversial (11-16). Detection of NT in vitro following exposure to synthetic peroxynitrite (ONOO Ϫ ) initially suggested that the reaction of NO with superoxide (O 2 Ϫ ) may be the primary source of NT (17,18). Further studies demonstrated that cogeneration of NO and O 2 Ϫ gave dissimilar results than bolus synthetic ONOO Ϫ (12,19,20). These disparities in nitration yields arose from further reactions of ONOO Ϫ with excess NO or O 2 Ϫ (21). Given the complexity of this seemingly simple reaction, much debate has ensued over the likelihood of NT formation under biologically relevant conditions (12,14).In addition to a ONOO Ϫ -mediated pathway, NT formation has been shown to result from the catalysis of nitrite oxidation by peroxidases, thus providing an alternate mechanism for its formation in vivo (22-24). Although leukocyte peroxidases likely account for a substantial amount of NT production in vivo, this mechanism fails to explain NT formation in the absence of inflammatory cells or peroxidases [i.e., a MPO Ϫ/Ϫ mouse model (25)].NT has been shown to occur on distinct proteins rather than in an indiscriminate manner (26). This may result from variations in protein susceptibility to nitration due to conformational differences or to association with redox active metals (27,28). We evaluated the relative efficacy of the synthetic ONOO Ϫ , NO͞O 2 Ϫ cogeneration, peroxidase, and redox active metal pathways to promote NT formation. Materials and MethodsBSA (essentially globulin-free), ribonuclease A, ferriprotoporphyrin IX (hemin), superoxide dismutase (SOD; bovine erythrocytes), cytochrome c, horseradish peroxidase (HRP), catalase (Cat), hypoxanthine (HX), myoglobin (horse heart), 2,2Ј-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), FeSO 4 , diethylenetriaminepentaacetic acid (DTPA), dimethylformamide (DMF), ␤-amyloid (1-42) protein (A␤), MnO 2 , and CuCl 2 were purchased from Sigma-Aldrich. H 2 O 2 , NaHCO 3 , NaNO 2 , and FeCl 3 were from Fisher Scientific....

NO synthase 2 ( NOS2 ) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

“…A fall in NO may be caused, in part, by a parallel increase in scavenging mechanisms for NO. For example, redox active iron accumulates in neurons in AD (42) and contributes to nitration of proteins such as A␤ (43). The process of nitration, in turn, represents conditions that reduce NO bioavailability and alter cell signaling pathways initiated by specific levels of NO.…”

1-Methyl-4-phenylpyridinium-induced Apoptosis in Cerebellar Granule Neurons Is Mediated by Transferrin Receptor Iron-dependent Depletion of Tetrahydrobiopterin and Neuronal Nitric-oxide Synthase-derived Superoxide

“…Nitration of tyrosines present in TfR has been proposed to modulate iron signaling (37). An increase in protein nitration was detected in the presence of ⅐ NO, H 2 O 2 , and iron (66). Peroxynitrite formation decreased ⅐ NO levels and enhanced the iron-mediated toxicity while decreasing the proteasomal function.…”

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

“…Depleted NO production in a transgenic-knockout (BERK) model is associated with increased tyrosine nitration [16], suggesting that hemolysis in this model may trigger the reported hemin-mediated nitrotyrosine formation in the presence of nitrite and hydrogen peroxide (H 2 O 2 ) [38]. L-arginine (a substrate for NO) and several NO donors can decrease the damage resulting from post-ischemic reperfusion [14].…”