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      Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine

      Proceedings of the National Academy of Sciences

      Proceedings of the National Academy of Sciences

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          Abstract

          <p id="d4269403e155">Aerobic life in humans imposes the hazard of excess oxidation in cell and tissue components that may compromise cell function and viability. The formation and accumulation of oxidized products in biomolecules such as proteins and lipids are observed in various pathologies and during the normal aging process. This review article aims to integrate some early and remarkable discoveries in the field, with more recent developments that helped to define a causative role of oxygen radicals, nitric oxide, and peroxynitrite in human physiology and pathology. These aspects of human redox biochemistry contribute to the understanding of the molecular basis of diseases and aging and open avenues for the development of preventive and therapeutic strategies in molecular medicine. </p><p class="first" id="d4269403e158">Oxygen-derived free radicals and related oxidants are ubiquitous and short-lived intermediates formed in aerobic organisms throughout life. These reactive species participate in redox reactions leading to oxidative modifications in biomolecules, among which proteins and lipids are preferential targets. Despite a broad array of enzymatic and nonenzymatic antioxidant systems in mammalian cells and microbes, excess oxidant formation causes accumulation of new products that may compromise cell function and structure leading to cell degeneration and death. Oxidative events are associated with pathological conditions and the process of normal aging. Notably, physiological levels of oxidants also modulate cellular functions via homeostatic redox-sensitive cell signaling cascades. On the other hand, nitric oxide ( <sup>•</sup>NO), a free radical and weak oxidant, represents a master physiological regulator via reversible interactions with heme proteins. The bioavailability and actions of <sup>•</sup>NO are modulated by its fast reaction with superoxide radical ( <span class="inline-formula"> <math id="i1" overflow="scroll"> <mrow> <msubsup> <mtext>O</mtext> <mn>2</mn> <mrow> <mo>•</mo> <mo>−</mo> </mrow> </msubsup> </mrow> </math> </span>), which yields an unusual and reactive peroxide, peroxynitrite, representing the merging of the oxygen radicals and <sup>•</sup>NO pathways. In this Inaugural Article, I summarize early and remarkable developments in free radical biochemistry and the later evolution of the field toward molecular medicine; this transition includes our contributions disclosing the relationship of <sup>•</sup>NO with redox intermediates and metabolism. The biochemical characterization, identification, and quantitation of peroxynitrite and its role in disease processes have concentrated much of our attention. Being a mediator of protein oxidation and nitration, lipid peroxidation, mitochondrial dysfunction, and cell death, peroxynitrite represents both a pathophysiologically relevant endogenous cytotoxin and a cytotoxic effector against invading pathogens. </p>

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          Most cited references 101

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          Superoxide radical and superoxide dismutases.

           I Fridovich (1995)
          O2- oxidizes the [4Fe-4S] clusters of dehydratases, such as aconitase, causing-inactivation and release of Fe(II), which may then reduce H2O2 to OH- +OH.. SODs inhibit such HO. production by scavengingO2-, but Cu, ZnSODs, by virtue of a nonspecific peroxidase activity, may peroxidize spin trapping agents and thus give the appearance of catalyzing OH. production from H2O2. There is a glycosylated, tetrameric Cu, ZnSOD in the extracellular space that binds to acidic glycosamino-glycans. It minimizes the reaction of O2- with NO. E. coli, and other gram negative microorganisms, contain a periplasmic Cu, ZnSOD that may serve to protect against extracellular O2-. Mn(III) complexes of multidentate macrocyclic nitrogenous ligands catalyze the dismutation of O2- and are being explored as potential pharmaceutical agents. SOD-null mutants have been prepared to reveal the biological effects of O2-. SodA, sodB E. coli exhibit dioxygen-dependent auxotrophies and enhanced mutagenesis, reflecting O2(-)-sensitive biosynthetic pathways and DNA damage. Yeast, lacking either Cu, ZnSOD or MnSOD, are oxygen intolerant, and the double mutant was hypermutable and defective in sporulation and exhibited requirements for methionine and lysine. A Cu, ZnSOD-null Drosophila exhibited a shortened lifespan.
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            Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide.

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              Peroxynitrite: biochemistry, pathophysiology and development of therapeutics.

              Peroxynitrite--the product of the diffusion-controlled reaction of nitric oxide with superoxide radical--is a short-lived oxidant species that is a potent inducer of cell death. Conditions in which the reaction products of peroxynitrite have been detected and in which pharmacological inhibition of its formation or its decomposition have been shown to be of benefit include vascular diseases, ischaemia-reperfusion injury, circulatory shock, inflammation, pain and neurodegeneration. In this Review, we first discuss the biochemistry and pathophysiology of peroxynitrite and then focus on pharmacological strategies to attenuate the toxic effects of peroxynitrite. These include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proc Natl Acad Sci USA
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                June 05 2018
                June 05 2018
                June 05 2018
                May 25 2018
                : 115
                : 23
                : 5839-5848
                Article
                10.1073/pnas.1804932115
                6003358
                29802228
                29d9ba51-2b8b-4e9d-a091-775cb18f5d11
                © 2018

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