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|Title:||Paramagnetic bradykinin analogues as substrates for angiotensin I-converting enzyme: Pharmacological and conformation studies|
|Authors:||Teixeira, Luis Gustavo de Deus [UNIFESP]|
Bersanetti, Patricia Alessandra [UNIFESP]
Carmona, Adriana Karaoglanovic [UNIFESP]
Nakaie, Clovis Ryuichi [UNIFESP]
Angiotensin I-converting enzyme
|Publisher:||Academic Press Inc Elsevier Science|
|Citation:||Bioorganic Chemistry. San Diego, v. 69, p. 159-166, 2016.|
|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.|
|Appears in Collections:||Artigo|
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