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

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Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.creatorRenck, Daiana-
Autor(es): dc.creatorDucati, Rodrigo G.-
Autor(es): dc.creatorPalma, Mario Sergio-
Autor(es): dc.creatorSantos, Diogenes S.-
Autor(es): dc.creatorBasso, Luiz A.-
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Descrição: dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)-
Descrição: dc.descriptionBanco Nacional de Desenvolvimento Econômico e Social (BNDES)-
Descrição: dc.descriptionCNPq: 304051/1975-06-
Descrição: dc.descriptionCNPq: 520182/99-5-
Descrição: dc.descriptionCNPq: 500079/90-0-
Descrição: dc.descriptionUridine 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.-
Formato: dc.format35-42-
Idioma: dc.languageen-
Publicador: dc.publisherElsevier B.V.-
Relação: dc.relationArchives of Biochemistry and Biophysics-
Relação: dc.relation3.118-
Relação: dc.relation1,350-
Direitos: dc.rightsclosedAccess-
Palavras-chave: dc.subjectCancer chemotherapy-
Palavras-chave: dc.subjectInitial velocity-
Palavras-chave: dc.subjectProduct inhibition-
Palavras-chave: dc.subjectFluorescence spectroscopy-
Palavras-chave: dc.subjectpH-rate profiles-
Palavras-chave: dc.subjectUridine phosphorylase kinetic mechanism-
Título: dc.titleThe kinetic mechanism of human uridine phosphorylase 1: Towards the development of enzyme inhibitors for cancer chemotherapy-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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