title: Urate hydroperoxide oxidizes human peroxiredoxin 1 and peroxiredoxin 2.
abstract: Urate hydroperoxide is a product of the oxidation of uric acid by inflammatory heme peroxidases. The formation of urate hydroperoxide might be a key event in vascular inflammation, where there is large amount of uric acid and inflammatory peroxidases. Urate hydroperoxide oxidizes glutathione and sulfur-containing amino acids and is expected to react fast toward reactive thiols from peroxiredoxins (Prxs). The kinetics for the oxidation of the cytosolic 2-Cys Prx1 and Prx2 revealed that urate hydroperoxide oxidizes these enzymes at rates comparable with hydrogen peroxide. The second-order rate constants of these reactions were 4.9 × 105and 2.3 × 106m-1s-1for Prx1 and Prx2, respectively. Kinetic and simulation data suggest that the oxidation of Prx2 by urate hydroperoxide occurs by a three-step mechanism, where the peroxide reversibly associates with the enzyme; then it oxidizes the peroxidatic cysteine, and finally, the rate-limiting disulfide bond is formed. Of relevance, the disulfide bond formation was much slower in Prx2 (k3= 0.31 s-1) than Prx1 (k3= 14.9 s-1). In addition, Prx2 was more sensitive than Prx1 to hyperoxidation caused by both urate hydroperoxide and hydrogen peroxide. Urate hydroperoxide oxidized Prx2 from intact erythrocytes to the same extent as hydrogen peroxide. Therefore, Prx1 and Prx2 are likely targets of urate hydroperoxide in cells. Oxidation of Prxs by urate hydroperoxide might affect cell function and be partially responsible for the pro-oxidant and pro-inflammatory effects of uric acid.
authors.affiliation: From the Departamento de Bioquímica, Instituto de Química (IQUSP).
authors.forename: Larissa A C
authors.initials: LAC
authors.lastname: Carvalho
authors.affiliation: From the Departamento de Bioquímica, Instituto de Química (IQUSP).
authors.forename: Daniela R
authors.initials: DR
authors.lastname: Truzzi
authors.affiliation: From the Departamento de Bioquímica, Instituto de Química (IQUSP).
authors.forename: Thamiris S
authors.initials: TS
authors.lastname: Fallani
authors.affiliation: Departamento de Genética e Biologia Evolutiva, Instituto de Biociências (IB-USP), and.
authors.forename: Simone V
authors.initials: SV
authors.lastname: Alves
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, São Paulo-SP CEP 05508-000, Brazil.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Toledo
authors.affiliation: From the Departamento de Bioquímica, Instituto de Química (IQUSP).
authors.forename: Ohara
authors.initials: O
authors.lastname: Augusto
authors.affiliation: Departamento de Genética e Biologia Evolutiva, Instituto de Biociências (IB-USP), and.
authors.forename: Luís E S
authors.initials: LES
authors.lastname: Netto
authors.affiliation: From the Departamento de Bioquímica, Instituto de Química (IQUSP), flaviam@iq.usp.br fcmeotti@gmail.com.
authors.forename: Flavia C
authors.initials: FC
authors.lastname: Meotti
mesh_terms: D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D004912:Erythrocytes / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D010084:Oxidation-Reduction; D010545:Peroxides / Q000737:chemistry* / Q000378:metabolism; D054464:Peroxiredoxins / Q000737:chemistry* / Q000378:metabolism; D014527:Uric Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004220:Disulfides; D010545:Peroxides; C000608134:urate hydroperoxide; D014527:Uric Acid; C515940:PRDX1 protein, human; C086065:PRDX2 protein, human; D054464:Peroxiredoxins
keywords: hydrogen peroxide; inflammation; oxidation-reduction (redox); peroxiredoxin; urate hydroperoxide; uric acid