The kinetic mechanism of human uridine phosphorylase 1: Towards the development of enzyme inhibitors for cancer chemotherapy

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dc.contributor.authorRenck, Daiana
dc.contributor.authorDucati, Rodrigo G.
dc.contributor.authorPalma, Mario Sergio [UNESP]
dc.contributor.authorSantos, Diogenes S.
dc.contributor.authorBasso, Luiz A.
dc.contributor.institutionPontifícia Universidade Católica do Rio Grande do Sul (PUCRS)
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.date.accessioned2014-05-20T13:55:20Z
dc.date.available2014-05-20T13:55:20Z
dc.date.issued2010-05-01
dc.description.abstractUridine phosphorylase (UP) is a key enzyme in the pyrimidine salvage pathway, catalyzing the reversible phosphorolysis of uridine to uracil and ribose-l-phosphate (R1P). The human UP type 1 (hUP1) is a molecular target for the design of inhibitors intended to boost endogenous uridine levels to rescue normal tissues from the toxicity of fluoropyrimidine nucleoside chemotherapeutic agents, such as capecitabine and 5-fluorouracil. Here, we describe a method to obtain homogeneous recombinant hUP1, and present initial velocity, product inhibition, and equilibrium binding data. These results suggest that hUP1 catalyzes uridine phosphorolysis by a steady-state ordered bi bi kinetic mechanism, in which inorganic phosphate binds first followed by the binding of uridine, and uracil dissociates first, followed by RIP release. Fluorescence titration at equilibrium showed cooperative binding of either Pi or RIP binding to hUP1. Amino acid residues involved in either catalysis or substrate binding were proposed based on pH-rate profiles. (C) 2010 Elsevier B.V. All rights reserved.en
dc.description.affiliationPontificia Univ Catolica Rio Grande Sul PUCRS, CPBMF, INCT TB, BR-90619900 Porto Alegre, RS, Brazil
dc.description.affiliationPontificia Univ Catolica Rio Grande Sul PUCRS, Programa Posgrad Biol Celular & Mol, BR-90619900 Porto Alegre, RS, Brazil
dc.description.affiliationUNESP, Lab Biol Estrutural & Zooquim, Ctr Estudos Insetos Sociais, Dept Biol,Inst Biociencias Rio Claro, Rio Claro, SP, Brazil
dc.description.affiliationUnespUNESP, Lab Biol Estrutural & Zooquim, Ctr Estudos Insetos Sociais, Dept Biol,Inst Biociencias Rio Claro, Rio Claro, SP, Brazil
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipBanco Nacional de Desenvolvimento Econômico e Social (BNDES)
dc.description.sponsorshipIdCNPq: 304051/1975-06
dc.description.sponsorshipIdCNPq: 520182/99-5
dc.description.sponsorshipIdCNPq: 500079/90-0
dc.format.extent35-42
dc.identifierhttp://dx.doi.org/10.1016/j.abb.2010.03.004
dc.identifier.citationArchives of Biochemistry and Biophysics. New York: Elsevier B.V., v. 497, n. 1-2, p. 35-42, 2010.
dc.identifier.doi10.1016/j.abb.2010.03.004
dc.identifier.issn0003-9861
dc.identifier.lattes2901888624506535
dc.identifier.urihttp://hdl.handle.net/11449/19806
dc.identifier.wosWOS:000277537800005
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofArchives of Biochemistry and Biophysics
dc.relation.ispartofjcr3.118
dc.relation.ispartofsjr1,350
dc.rights.accessRightsAcesso restrito
dc.sourceWeb of Science
dc.subjectCancer chemotherapyen
dc.subjectInitial velocityen
dc.subjectProduct inhibitionen
dc.subjectFluorescence spectroscopyen
dc.subjectpH-rate profilesen
dc.subjectUridine phosphorylase kinetic mechanismen
dc.titleThe kinetic mechanism of human uridine phosphorylase 1: Towards the development of enzyme inhibitors for cancer chemotherapyen
dc.typeArtigo
dcterms.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dcterms.rightsHolderElsevier B.V.
unesp.author.lattes2901888624506535
unesp.author.orcid0000-0002-7363-8211[3]
unesp.author.orcid0000-0003-0903-2407[5]
unesp.campusUniversidade Estadual Paulista (Unesp), Instituto de Biociências, Rio Claropt

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Artigos - Biologia - IBRC