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Oxygen Radicals, Nitric Oxide, and Peroxynitrite: Redox INAUGURAL ARTICLE Pathways in Molecular Medicine

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Oxygen Radicals, Nitric Oxide, and Peroxynitrite: Redox INAUGURAL ARTICLE Pathways in Molecular Medicine Oxygen radicals, nitric oxide, and peroxynitrite: Redox INAUGURAL ARTICLE pathways in molecular medicine Rafael Radia,b,1 aDepartamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; and bCenter for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2015. Contributed by Rafael Radi, April 23, 2018 (sent for review March 21, 2018; reviewed by Edward M. De Robertis, Irwin Fridovich, and Michael A. Marletta) Â Ã Oxygen-derived free radicals and related oxidants are ubiquitous and •− • d O dt = k½R ½O2, [2] short-lived intermediates formed in aerobic organisms throughout 2 • life. These reactive species participate in redox reactions leading to where R represents electron donors present in different cellular oxidative modifications in biomolecules, among which proteins and and extracellular compartments. lipids are preferential targets. Despite a broad array of enzymatic and Although these early proposals seemed reasonable, the actual nonenzymatic antioxidant systems in mammalian cells and microbes, demonstration of the biological formation of oxygen radicals, and in excess oxidant formation causes accumulation of new products that •− “ particular O2 ,was reached gradually and as the result of travel- may compromise cell function and structure leading to cell degener- ling a tortuous path,” as indicated by Irwin Fridovich (3). Indeed, ation and death. Oxidative events are associated with pathological the idea of a continuous and endogenous formation of unstable and conditions and the process of normal aging. Notably, physiological potentially toxic intermediates derived from oxidative metabolism levels of oxidants also modulate cellular functions via homeostatic was initially difficult to accept. Much of the early mechanistic work redox-sensitive cell signaling cascades. On the other hand, nitric oxide •− • on the biochemistry of O2 formation had to do with understanding ( NO), a free radical and weak oxidant, represents a master physio- the enzymology of an enzyme, xanthine oxidase (XO), that partic- logical regulator via reversible interactions with heme proteins. The • ipates in the last step of purine catabolism in mammals; XO cata- bioavailability and actions of NO are modulated by its fast reaction BIOCHEMISTRY •− lyzes the oxidation of hypoxanthine and xanthine to uric acid with superoxide radical (O2 ), which yields an unusual and reactive utilizing molecular oxygen as cosubstrate (Fig. 1, Upper part). •− peroxide, peroxynitrite, representing the merging of the oxygen rad- Indeed, circumstantial evidence of O generation during the • 2 icals and NO pathways. In this Inaugural Article, I summarize early aerobic oxidation of xanthine by XO was obtained in experiments in and remarkable developments in free radical biochemistry and the 2− which added sulfite (SO3 ) was oxidized (4). Sulfite oxidation pro- later evolution of the field toward molecular medicine; this transition •− • ceeded through a free radical process initiated by XO-derived O2 includes our contributions disclosing the relationship of NO with re- to yield the sulfur trioxy radical, which, in turn, reacts with molecular dox intermediates and metabolism. The biochemical characterization, oxygen evolving to peroxymonosulfate radical anion (5, 6): identification, and quantitation of peroxynitrite and its role in disease processes have concentrated much of our attention. Being a mediator 2− •− + •− SO + O + 2H → SO + H2O2, [3] of protein oxidation and nitration, lipid peroxidation, mitochondrial 3 2 3 dysfunction, and cell death, peroxynitrite represents both a patho- •− + → •− [4] physiologically relevant endogenous cytotoxin and a cytotoxic effec- SO3 O2 SO5 . tor against invading pathogens. •− SO5 is a strong one-electron oxidant and serves to propagate free radicals | nitric oxide | peroxynitrite | oxidation | the free radical chain reaction (5). The additional oxygen con- protein tyrosine nitration sumption secondary to sulfite oxidation in the XO-catalyzed re- actions was utilized for the development of an ultrasensitive he toxicity of endogenously formed oxygen radicals in bi- Significance Tological systems was initially substantiated in studies of “ox- ygen poisoning” parallel to the discovery of the mechanisms of radiation-induced injury (1). (A free radical is a molecule con- Aerobiclifeinhumansimposesthe hazard of excess oxidation in cell and tissue components that may compromise cell function and taining an unpaired electron in its external molecular orbital; viability. The formation and accumulation of oxidized products in typically, radicals are reactive and short-lived intermediates.) biomolecules such as proteins and lipids are observed in various Indeed, oxygen radicals arising from the radiolysis of water such • •− pathologies and during the normal aging process. This review ar- as hydroxyl radicals ( OH) and superoxide radicals (O ) and, • 2 ticle aims to integrate some early and remarkable discoveries in the later, peroxyl radicals (ROO ) were identified as key mediators field, with more recent developments that helped to define a of the actions of ionizing radiation (2). In the 1950s, an in- causative role of oxygen radicals, nitric oxide, and peroxynitrite in creasing body of evidence pointed to the biological formation of human physiology and pathology. These aspects of human redox oxygen radicals associated with cell redox metabolism starting biochemistry contribute to the understanding of the molecular with the monovalent reduction of molecular oxygen by electron basis of diseases and aging and open avenues for the development •− of preventive and therapeutic strategies in molecular medicine. transfer proteins or endogenous reductants to yield O2 : − •− + e → [1] Author contributions: R.R. analyzed data and wrote the paper. O2 O2 . Reviewers: E.M.D.R., Howard Hughes Medical Institute and University of California, Los Angeles; I.F., Duke University Medical Center; and M.A.M., University of California, Berkeley. Oxygen Radicals: From Radiation Chemistry to Metabolism The author declares no conflict of interest. Seminal works such as refs. 1 and 2 opened the hypothesis that Published under the PNAS license. •− 1 the rate of O2 formation in tissues would increase as a function Email: [email protected]. of oxygen concentration as follows: www.pnas.org/cgi/doi/10.1073/pnas.1804932115 PNAS Latest Articles | 1of10 Downloaded by guest on September 25, 2021 Fig. 1. Xanthine oxidase-catalyzed purine oxidation, oxygen radical formation, and luminol chemiluminescence. enzyme assay (4) and also to reveal free radical formation from Xanthine Oxidase and Chemiluminescence: Early Work on other enzymatic reactions (7). Free Radicals Some years later, it was also demonstrated that XO was + At about the same period that Fridovich and Handler at Duke capable of reducing ferric cytochrome c (cyt c3 )byan •− University were characterizing the formation of free radicals O2 -dependent process (reviewed in ref. 3): generated during the aerobic oxidation of xanthine by XO (4, 15), related experiments were carried out at the Facultad de c3+ + •−→ c2+ + [5] cyt O2 cyt O2. Medicina, Universidad de la República in Montevideo, Uruguay, under the leadership of the American biochemist John R. Totter 3 5 •− – (As deducted from Eqs. and ,O2 can behave both as a one- (1914 2001), who arrived at the Department of Biochemistry as a electron oxidant and reductant.) The biochemical characteriza- visiting professor under the auspices of the Rockefeller Founda- tion of the XO-dependent reduction of cytochrome c constituted tion during the period of 1958–1960; Prof. Totter was an experi- •− enced investigator in chemiluminescence and XO enzymology and the foundation for the discovery of the O2 catabolizing enzyme, Cu/Zn-containing superoxide dismutase (Cu/Zn-SOD), which had previously been a scientist of the Oak Ridge National Labo- competed with the cytochrome c reduction process (8) by the ratory (in Tennessee) and the Atomic Energy Commission (in following reaction: Washington, DC). (Historical information about John R. Totter can be found at ethw.org/John_Totter and https://ehss.energy.gov/ •− + •− + + SOD! + [6] ohre/roadmap/histories/0481/0481toc.html#0481_part.) The arrival O2 O2 2H H2O2 O2. of Dr. Totter in Montevideo resulted in the vigorous incorporation of instruments and modern biochemical research in our de- The discovery of an enzyme capable of the enzymatic elimination •− partment, and he initiated studies in the area of free radical and of O at rates approaching the diffusion-controlled limit (k = 2 − − redox biochemistry. Indeed, Totter and a young group of collab- 2 × 109 M 1·s 1) represented a fundamental step to further es- •− orators focused on biochemical studies to characterize the for- tablish the idea of the endogenous formation of O2 in cells and mation of reactive oxygen species generated during the catalytic the need to keep its steady-state levels low, to minimize toxicity action of XO through the utilization of chemiluminescence probes, due to uncontrolled oxidation reactions on biological targets. namely luminol (5-amino-2,3-dihydrophthalazine-1,4-dione) and [The action of SODs has to be complemented with an array of lucigenin [10-methyl-9-(10-methylacridin-10-ium-9-yl)acridin-10-ium enzymatic H2O2-detoxifying
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