beta-Amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)

Clayton, Daniel, Hanchapola, Iresha, Hausler, Nicholas, Unabia, Sharon, Lew, Rebecca A., Widdop, Robert E., Smith, Alexander I., Perlmutter, Patrick and Aguilar, Marie-Isabel (2011) beta-Amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2). Journal of Molecular Recognition, 24 2: 235-244. doi:10.1002/jmr.1041


Author Clayton, Daniel
Hanchapola, Iresha
Hausler, Nicholas
Unabia, Sharon
Lew, Rebecca A.
Widdop, Robert E.
Smith, Alexander I.
Perlmutter, Patrick
Aguilar, Marie-Isabel
Title beta-Amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)
Formatted title
β-Amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)
Journal name Journal of Molecular Recognition   Check publisher's open access policy
ISSN 0952-3499
1099-1352
Publication date 2011-03
Year available 2010
Sub-type Article (original research)
DOI 10.1002/jmr.1041
Volume 24
Issue 2
Start page 235
End page 244
Total pages 10
Place of publication Bognor Regis, West Sussex, U.K.
Publisher John Wiley & Sons
Collection year 2012
Language eng
Formatted abstract
In spite of the important role of angiotensin converting enzyme 2 (ACE2) in the cardiovascular system, little is known about the substrate structural requirements of the AngII–ACE2 interaction. Here we investigate how changes in angiotensin II (AngII) structure affect binding and cleavage by ACE2. A series of C3 β-amino acid AngII analogs were generated and their secondary structure, ACE2 inhibition, and proteolytic stability assessed by circular dichroism (CD), quenched fluorescence substrate (QFS) assay, and LC-MS analysis, respectively. The β-amino acid-substituted AngII analogs showed differences in secondary structure, ACE2 binding and proteolytic stability. In particular, three different subsets of structure-activity profiles were observed corresponding to substitutions in the N-terminus, the central region and the C-terminal region of AngII. The results show that β-substitution can dramatically alter the structure of AngII and changes in structure correlated with ACE2 inhibition and/or substrate cleavage. β-amino acid substitution in the N-terminal region of AngII caused little change in structure or substrate cleavage, while substitution in the central region of AngII lead to increased β-turn structure and enhanced substrate cleavage. β-amino acid substitution in the C-terminal region significantly diminished both secondary structure and proteolytic processing by ACE2. The β-AngII analogs with enhanced or decreased proteolytic stability have potential application for therapeutic intervention in cardiovascular disease.
Keyword Angiotensin converting enzyme-2
Angiotensin II
β-amino acids
beta-amino acids
Substrate conformation
Circular dichroism
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ
Additional Notes Article first published online: 14 JUN 2010.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 20 Mar 2012, 14:27:06 EST by Susan Allen on behalf of Institute for Molecular Bioscience