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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Pharmacological Activities and Hydrolysis by Peptidases of [Phospho-Ser(6)]-Bradykinin (pS(6)-BK)

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Autor(es):
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Assis, Diego M. [1] ; Juliano, Luiz [1] ; Paschoalin, Thaysa [1] ; Kouyoumdjian, Maria [2] ; Calixto, Joao B. [3] ; Santos, Robson A. S. [4] ; Pertinhez, Thelma A. [5] ; Gauthier, Francis [6] ; Moreau, Thierry [6] ; Blaber, Michael [7] ; Juliano, Maria A. [1]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Univ Fed Sao Paulo, Escola Paulista Med, Dept Biophys, Sao Paulo, SP - Brazil
[2] Univ Fed Sao Paulo, Dept Biochem Biophys & Med, Sao Paulo, SP - Brazil
[3] Univ Fed Santa Catarina, Dept Pharmacol, Florianopolis, SC - Brazil
[4] Univ Fed Minas Gerais, Dept Physiol & Biophys, Belo Horizonte, MG - Brazil
[5] Arcispedale Santa Maria Nuova IRCCS, Transfus Med Unit, Reggio Emilia - Italy
[6] Univ Tours, UMR INSERM U1100, F-37041 Tours - France
[7] Florida State Univ, Coll Med, Dept Biomed Sci, Tallahassee, FL 32306 - USA
Número total de Afiliações: 7
Tipo de documento: Artigo Científico
Fonte: Biochemical Pharmacology; v. 97, n. 2, p. 203-214, SEP 15 2015.
Citações Web of Science: 2
Resumo

Phosphorylated kininogen and some of its fragments containing serine phosphorylated bradykinin ({[}pS(6)]-Bk) were identified in human serum and plasma by a phosphoproteomic approach. We report the kininogenase ability of human tissue and plasma kallikreins and tryptase to generate {[}pS(6)]-Bk or Lys-{[}pS(6)]-Bk having as substrate the synthetic human kininogen fluorescent fragment Abz-MISLMKRPPGF {[}pS(386)]PFRSSRI-NH2. The pharmacological assays of {[}pS(6)]-Bk showed it as a full B2 bradykinin receptor agonist in smooth muscle, it produces a portal liver hypertensive response in rat and mouse paw edema that lasts longer than Bk. The rat hypotensive response to infusions of Bk is greater than that of {[}pS(6)]Bk, both if injected through femoral vein or aorta. {[}pS(6)]-Bk was more resistant than Bk to kininase digestion performed with angiotensin converting enzyme, neprilysin, thimet oligopeptidase, aminopeptidase P and carboxypeptidase M. H-1-NMR experiments indicated that {[}pS(6)]-Bk has lower flexibility, with the pS(6)-P-7 bond restricted to the trans conformation, and can explain {[}pS(6)]-Bk resistance to hydrolysis. In conclusion, {[}pS(6)]-Bk presenting lower activity than Bk, with longer lasting effects and being slowly released by kininogenases from synthetic Abz-MISLMKRPPGF{[}pS(386)]PFRSSRI-NH2, suggests that phosphorylation of the kininogens can be an efficient kallikrein-kinin system regulator. (C) 2015 Elsevier Inc. All rights reserved. (AU)

Processo FAPESP: 12/50191-4 - Síntese, estudo cinético e aplicações de substratos e inibidores de enzimas proteolíticas
Beneficiário:Maria Aparecida Juliano
Modalidade de apoio: Auxílio à Pesquisa - Temático