Peroxiredoxin Functions as a Peroxidase and a Regulator and Sensor of Local Peroxides

Abstract

Peroxiredoxins (Prxs) contain an active site cysteine that is sensitive to oxidation by H2O2. Mammalian cells express six Prx isoforms that are localized to various cellular compartments. The oxidized active site cysteine of Prx can be reduced by a cellular thiol, thus enabling Prx to function as a locally constrained peroxidase. Regulation of Prx via phosphorylation in response to extracellular signals allows the local accumulation of H2O2 and thereby enables its messenger function. The fact that the oxidation state of the active site cysteine of Prx can be transferred to other proteins that are less intrinsically susceptible to H2O2 also allows Prx to function as an H2O2 sensor. Peroxiredoxins (Prxs) contain an active site cysteine that is sensitive to oxidation by H2O2. Mammalian cells express six Prx isoforms that are localized to various cellular compartments. The oxidized active site cysteine of Prx can be reduced by a cellular thiol, thus enabling Prx to function as a locally constrained peroxidase. Regulation of Prx via phosphorylation in response to extracellular signals allows the local accumulation of H2O2 and thereby enables its messenger function. The fact that the oxidation state of the active site cysteine of Prx can be transferred to other proteins that are less intrinsically susceptible to H2O2 also allows Prx to function as an H2O2 sensor. IntroductionAn unusual antioxidant protein, now called peroxiredoxin (Prx), 2The abbreviations used are: PrxperoxiredoxinROSreactive oxygen speciesTrxthioredoxinCPperoxidatic CysCRresolving CysERendoplasmic reticulumSrxsulfiredoxinKOknock-outPTPprotein-tyrosine phosphatasePTKprotein-tyrosine kinaseNoxNADPH oxidasePDIprotein-disulfide isomerasePLA2phospholipase A2. was initially identified on the basis of its capacity to protect proteins from oxidative damage induced by reactive oxygen species (ROS) produced in the presence of DTT. It was named “protector protein” or “thiol-specific antioxidant” before being renamed Prx (1Kim I.H. Kim K. Rhee S.G. Induction of an antioxidant protein of Saccharomyces cerevisiae by O2, Fe3+, or 2-mercaptoethanol.Proc. Natl. Acad. Sci. U.S.A. 1989; 86: 6018-6022Crossref PubMed Scopus (131) Google Scholar, 2Kim K. Kim I.H. Lee K.Y. Rhee S.G. Stadtman E.R. The isolation and purification of a specific “protector” protein which inhibits enzyme inactivation by a thiol/Fe(III)/O2 mixed-function oxidation system.J. Biol. Chem. 1988; 263: 4704-4711Abstract Full Text PDF PubMed Google Scholar, 3Chae H.Z. Kim I.H. Kim K. Rhee S.G. Cloning, sequencing, and mutation of thiol-specific antioxidant gene of Saccharomyces cerevisiae.J. Biol. Chem. 1993; 268: 16815-16821Abstract Full Text PDF PubMed Google Scholar, 4Chae H.Z. Robison K. Poole L.B. Church G. Storz G. Rhee S.G. Cloning and sequencing of thiol-specific antioxidant from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidant define a large family of antioxidant enzymes.Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 7017-7021Crossref PubMed Scopus (696) Google Scholar, 5Rhee S.G. Woo H.A. Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones.Antioxid. Redox Signal. 2011; 15: 781-794Crossref PubMed Scopus (324) Google Scholar). The ROS were generated as the result of the reduction of molecular oxygen by DTT to superoxide and H2O2, which were further reduced to hydroxyl radicals in the presence of trace amounts of contaminating metal (iron or copper) ions (6Kim K. Rhee S.G. Stadtman E.R. Nonenzymatic cleavage of proteins by reactive oxygen species generated by dithiothreitol and iron.J. Biol. Chem. 1985; 260: 15394-15397Abstract Full Text PDF PubMed Google Scholar). Analysis of purified yeast Prx revealed that it did not contain conventional redox centers such as metals, heme, flavin, or selenocysteine. Prx therefore did not resemble any antioxidant known at the time. It was subsequently found that (i) Prx is present in all biological kingdoms from bacteria to mammals; (ii) two cysteine residues, corresponding to Cys47 and Cys170 of yeast Prx, are highly conserved among Prx family members; (iii) Prxs are homodimers arranged in a head-to-tail orientation; and (iv) Cys47–SH of Prx is specifically oxidized by H2O2 to cysteine sulfenic acid (Cys–SOH), which is resolved by reaction with Cys170–SH of the adjacent monomer, resulting in the formation of a disulfide linkage, Cys47–S-S–Cys170 (7Chae H.Z. Rhee S.G. of thiol-specific antioxidant and the of cysteine Natl. Acad. Sci. U.S.A. 1994; 91: PubMed Scopus Google Scholar). The antioxidant function of Prx was to the fact that the disulfide be reduced by resulting in of a was to be the biological of the function of Prx H.Z. Rhee S.G. reductase from Biol. Chem. 1994; Full Text PDF PubMed Google with in to H2O2 and also being found to be reduced by Prx reductase of PubMed Scopus Google Scholar). The conserved corresponding to Cys47 of yeast Prx was to as the to its to oxidation by and the conserved corresponding to Cys170 was the Poole L.B. and the of PubMed Scopus Google that H2O2 with the of oxidation of cysteine is by a that the of cysteine to a The of the of of the Prx family are in the of G. and sulfenic acid oxidation of the peroxiredoxin from and PubMed Scopus Google Scholar, Poole L.B. the peroxiredoxin PubMed Scopus Google Scholar, of yeast and with and by Biol. PubMed Scopus Google Scholar, The of peroxiredoxin with H2O2 is not in its reaction with other and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, G. of and in the of PubMed Scopus Google Scholar, and function of the mammalian Redox Signal. 2011; 15: PubMed Scopus Google Scholar). with H2O2 with a of the and of reactive oxygen Chem. Biol. PubMed Scopus Google the of Prxs with H2O2 with of to The of peroxiredoxin with H2O2 is not in its reaction with other and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, the and of reactive oxygen Chem. Biol. PubMed Scopus Google Scholar). The thus to be to the of Prx with The was to the fact that Prx not the of also the via a by and or conserved in the active site of all Prx K. Poole L.B. the and of Redox Signal. 2011; 15: PubMed Scopus Google of the basis of the or of the Prxs are and Prx H.Z. Robison K. Poole L.B. Church G. Storz G. Rhee S.G. Cloning and sequencing of thiol-specific antioxidant from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidant define a large family of antioxidant enzymes.Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 7017-7021Crossref PubMed Scopus (696) Google Scholar, 5Rhee S.G. Woo H.A. Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones.Antioxid. Redox Signal. 2011; 15: 781-794Crossref PubMed Scopus (324) Google Scholar, S.G. H.Z. Kim K. a and of and in Biol. PubMed Scopus Google Scholar). Mammalian cells express six isoforms of Prx isoforms Prx and Prx isoforms in with Prx and being localized in the Prx being to Prx being found in the and Prx being present in the and Prx is being on the and reaction of mammalian Prx are in with yeast Prx, the conserved of Prx is oxidized by H2O2 to the disulfide is with and is reduced by of the Prx are from in that contain two and the of to and thereby disulfide formation Poole L.B. and the of PubMed Scopus Google Scholar, K. Poole L.B. the and of Redox Signal. 2011; 15: PubMed Scopus Google Scholar, Poole L.B. and of Sci. Full Text Full Text PDF PubMed Scopus Google Scholar). a of Prxs can with a H2O2 and to cysteine acid before it is to with Woo H.A. H.Z. Kim K. Rhee S.G. of peroxiredoxin as the result of the oxidation of the site cysteine to cysteine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, of cellular response to oxidative in of at active Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in the inactivation of and in the formation of molecular that protein function Lee Lee Lee Kim Rhee S.G. Lee in two yeast oxidative from a to a molecular Full Text Full Text PDF PubMed Scopus Google Scholar, Kim Lee Kim Lee Kim Lee and of a peroxiredoxin that to Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Woo H.A. Kim Rhee S.G. Kim K. H.Z. oxidation of the cysteine of peroxiredoxin to acid molecular Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of Prxs can be reduced in an reaction by reduction of cysteine acid by cerevisiae PubMed Scopus Google Scholar). that Prxs from contain the and and at the of peroxiredoxin in sensitive to oxidative Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and that express a protein in oxidative and in the reduction of the of peroxiredoxin in the 2011; PubMed Scopus Google and the mammalian of the and Prx also in an Rhee S.G. of a enzyme at Biol. 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IntroductionAn unusual antioxidant protein, now called peroxiredoxin (Prx), 2The abbreviations used are: PrxperoxiredoxinROSreactive oxygen speciesTrxthioredoxinCPperoxidatic CysCRresolving CysERendoplasmic reticulumSrxsulfiredoxinKOknock-outPTPprotein-tyrosine phosphatasePTKprotein-tyrosine kinaseNoxNADPH oxidasePDIprotein-disulfide isomerasePLA2phospholipase A2. was initially identified on the basis of its capacity to protect proteins from oxidative damage induced by reactive oxygen species (ROS) produced in the presence of DTT. It was named “protector protein” or “thiol-specific antioxidant” before being renamed Prx (1Kim I.H. Kim K. Rhee S.G. Induction of an antioxidant protein of Saccharomyces cerevisiae by O2, Fe3+, or 2-mercaptoethanol.Proc. Natl. Acad. Sci. U.S.A. 1989; 86: 6018-6022Crossref PubMed Scopus (131) Google Scholar, 2Kim K. Kim I.H. Lee K.Y. Rhee S.G. Stadtman E.R. The isolation and purification of a specific “protector” protein which inhibits enzyme inactivation by a thiol/Fe(III)/O2 mixed-function oxidation system.J. Biol. Chem. 1988; 263: 4704-4711Abstract Full Text PDF PubMed Google Scholar, 3Chae H.Z. Kim I.H. Kim K. Rhee S.G. Cloning, sequencing, and mutation of thiol-specific antioxidant gene of Saccharomyces cerevisiae.J. Biol. Chem. 1993; 268: 16815-16821Abstract Full Text PDF PubMed Google Scholar, 4Chae H.Z. Robison K. Poole L.B. Church G. Storz G. Rhee S.G. Cloning and sequencing of thiol-specific antioxidant from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidant define a large family of antioxidant enzymes.Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 7017-7021Crossref PubMed Scopus (696) Google Scholar, 5Rhee S.G. Woo H.A. Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones.Antioxid. Redox Signal. 2011; 15: 781-794Crossref PubMed Scopus (324) Google Scholar). The ROS were generated as the result of the reduction of molecular oxygen by DTT to superoxide and H2O2, which were further reduced to hydroxyl radicals in the presence of trace amounts of contaminating metal (iron or copper) ions (6Kim K. Rhee S.G. Stadtman E.R. Nonenzymatic cleavage of proteins by reactive oxygen species generated by dithiothreitol and iron.J. Biol. Chem. 1985; 260: 15394-15397Abstract Full Text PDF PubMed Google Scholar). Analysis of purified yeast Prx revealed that it did not contain conventional redox centers such as metals, heme, flavin, or selenocysteine. Prx therefore did not resemble any antioxidant known at the time. It was subsequently found that (i) Prx is present in all biological kingdoms from bacteria to mammals; (ii) two cysteine residues, corresponding to Cys47 and Cys170 of yeast Prx, are highly conserved among Prx family members; (iii) Prxs are homodimers arranged in a head-to-tail orientation; and (iv) Cys47–SH of Prx is specifically oxidized by H2O2 to cysteine sulfenic acid (Cys–SOH), which is resolved by reaction with Cys170–SH of the adjacent monomer, resulting in the formation of a disulfide linkage, Cys47–S-S–Cys170 (7Chae H.Z. Rhee S.G. of thiol-specific antioxidant and the of cysteine Natl. Acad. Sci. U.S.A. 1994; 91: PubMed Scopus Google Scholar). The antioxidant function of Prx was to the fact that the disulfide be reduced by resulting in of a was to be the biological of the function of Prx H.Z. Rhee S.G. reductase from Biol. Chem. 1994; Full Text PDF PubMed Google with in to H2O2 and also being found to be reduced by Prx reductase of PubMed Scopus Google Scholar). The conserved corresponding to Cys47 of yeast Prx was to as the to its to oxidation by and the conserved corresponding to Cys170 was the Poole L.B. and the of PubMed Scopus Google that H2O2 with the of oxidation of cysteine is by a that the of cysteine to a The of the of of the Prx family are in the of G. and sulfenic acid oxidation of the peroxiredoxin from and PubMed Scopus Google Scholar, Poole L.B. the peroxiredoxin PubMed Scopus Google Scholar, of yeast and with and by Biol. PubMed Scopus Google Scholar, The of peroxiredoxin with H2O2 is not in its reaction with other and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, G. of and in the of PubMed Scopus Google Scholar, and function of the mammalian Redox Signal. 2011; 15: PubMed Scopus Google Scholar). with H2O2 with a of the and of reactive oxygen Chem. Biol. PubMed Scopus Google the of Prxs with H2O2 with of to The of peroxiredoxin with H2O2 is not in its reaction with other and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, the and of reactive oxygen Chem. Biol. PubMed Scopus Google Scholar). The thus to be to the of Prx with The was to the fact that Prx not the of also the via a by and or conserved in the active site of all Prx K. Poole L.B. the and of Redox Signal. 2011; 15: PubMed Scopus Google Scholar).