Paramagnetic bradykinin analogues as substrates for angiotensin I-converting enzyme: Pharmacological and conformation studies

Paramagnetic bradykinin analogues as substrates for angiotensin I-converting enzyme: Pharmacological and conformation studies

Author Teixeira, Luis Gustavo de Deus Autor UNIFESP Google Scholar
Malavolta, Luciana Google Scholar
Bersanetti, Patricia Alessandra Autor UNIFESP Google Scholar
Schreier, Shirley Google Scholar
Carmona, Adriana Karaoglanovic Autor UNIFESP Google Scholar
Nakaie, Clovis Ryuichi Autor UNIFESP Google Scholar
Abstract This study uses EPR, CD, and fluorescence spectroscopy to examine the structure of bradykinin (BK) analogues attaching the paramagnetic amino acid-type Toac (2,2,6,6-tetramethylpiperidine-1-oxyl-4-a mino-4-carboxylic acid) at positions 0, 3, 7, and 9. The data were correlated with the potencies in muscle contractile experiments and the substrate properties towards the angiotensin I-converting enzyme (ACE). A study of the biological activities in guinea pig ileum and rat uterus indicated that only Toac(0)-BK partially maintained its native biological potency among the tested peptides. This and its counterpart, Toac3-BK, maintained the ability to act as ACE substrates. These results indicate that peptides bearing Toac probe far from the ACE cleavage sites were more susceptible to hydrolysis by ACE. The results also emphasize the existence of a finer control for BK-receptor interaction than for BK binding at the catalytic site of this metallodipetidase. The kinetic kcat/ Km values decreased from 202.7 to 38.9 mu M-1 min(-1) for BK and Toac3-BK, respectively. EPR, CD, and fluorescence experiments reveal a direct relationship between the structure and activity of these paramagnetic peptides. In contrast to the turn-folded structures of the Toac-internally labeled peptides, more extended conformations were displayed by N-or C-terminally Toac-labeled analogues. Lastly, this work supports the feasibility of monitoring the progress of the ACE-hydrolytic process of Toac-attached peptides by examining time-dependent EPR spectral variations. (C) 2016 Elsevier Inc. All rights reserved.
Keywords Bradykinin
Angiotensin I-converting enzyme
Spin label
Biological activity
xmlui.dri2xhtml.METS-1.0.item-coverage San Diego
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Date 2016
Published in Bioorganic Chemistry. San Diego, v. 69, p. 159-166, 2016.
ISSN 0045-2068 (Sherpa/Romeo, impact factor)
Publisher Academic Press Inc Elsevier Science
Extent 159-166
Access rights Closed access
Type Article
Web of Science ID WOS:000387978900017

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