Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

12 Issues per year


IMPACT FACTOR 2016: 3.273

CiteScore 2016: 3.01

SCImago Journal Rank (SJR) 2016: 1.679
Source Normalized Impact per Paper (SNIP) 2016: 0.800

Online
ISSN
1437-4315
See all formats and pricing
More options …
Volume 388, Issue 4 (Apr 2007)

Issues

Insulin-regulated aminopeptidase: analysis of peptide substrate and inhibitor binding to the catalytic domain

Siying Ye
  • Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australia and Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Siew Yeen Chai / Rebecca A. Lew
  • Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Anthony L. Albiston
Published Online: 2007-03-28 | DOI: https://doi.org/10.1515/BC.2007.044

Abstract

Peptide inhibitors of insulin-regulated aminopeptidase (IRAP) accelerate spatial learning and facilitate memory retention and retrieval by binding competitively to the catalytic site of the enzyme and inhibiting its catalytic activity. IRAP belongs to the M1 family of Zn2+-dependent aminopeptidases characterized by a catalytic domain that contains two conserved motifs, the HEXXH(X)18E Zn2+-binding motif and the GXMEN exopeptidase motif. To elucidate the role of GXMEN in binding peptide substrates and competitive inhibitors, site-directed mutagenesis was performed on the motif. Non-conserved mutations of residues G428, A429 and N432 resulted in mutant enzymes with altered catalytic activity, as well as divergent changes in kinetic properties towards the synthetic substrate leucine β-naphthalamide. The affinities of the IRAP inhibitors angiotensin IV, Nle1-angiotensin IV, and LVV-hemorphin-7 were selectively decreased. Substrate degradation studies using the in vitro substrates vasopressin and Leu-enkephalin showed that replacement of G428 by either D, E or Q selectively abolished the catalysis of Leu-enkephalin, while [A429G]IRAP and [N432A]IRAP mutants were incapable of cleaving both substrates. These mutational studies indicate that G428, A429 and N432 are important for binding of both peptide substrates and inhibitors, and confirm previous results demonstrating that peptide IRAP inhibitors competitively bind to its catalytic site.

Keywords: aminopeptidase; angiotensin IV; AT4 receptor; IRAP; memory

About the article

Corresponding author


Received: October 18, 2006

Accepted: January 9, 2007

Published Online: 2007-03-28

Published in Print: 2007-04-01


Citation Information: Biological Chemistry, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2007.044.

Export Citation

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Masato Maruyama, Naomi Arisaka, Yoshikuni Goto, Yosuke Ohsawa, Hideshi Inoue, Hiroshi Fujiwara, Akira Hattori, and Masafumi Tsujimoto
Journal of Biological Chemistry, 2009, Volume 284, Number 50, Page 34692
[2]
Hanna Andersson and Mathias Hallberg
International Journal of Hypertension, 2012, Volume 2012, Page 1
[3]
Lorien J. Parker, David B. Ascher, Chen Gao, Luke A. Miles, Hugh H. Harris, and Michael W. Parker
Journal of Inorganic Biochemistry, 2012, Volume 115, Page 138
[4]
Richard J. Bodnar
Peptides, 2008, Volume 29, Number 12, Page 2292
[6]
Viet-Laï Pham, Cécile Gouzy-Darmon, Julien Pernier, Chantal Hanquez, Vivian Hook, Margery C. Beinfeld, Pierre Nicolas, Catherine Etchebest, Thierry Foulon, and Sandrine Cadel
Biochimie, 2011, Volume 93, Number 4, Page 730
[7]
Harald John, Stefanie John, and Wolf‐Georg Forssmann
Journal of Peptide Science, 2008, Volume 14, Number 7, Page 797
[8]
Masafumi Tsujimoto, Yoshikuni Goto, Masato Maruyama, and Akira Hattori
Heart Failure Reviews, 2008, Volume 13, Number 3, Page 285
[9]
Bart Stragier, Dimitri De Bundel, Sophie Sarre, Ilse Smolders, Georges Vauquelin, Alain Dupont, Yvette Michotte, and Patrick Vanderheyden
Heart Failure Reviews, 2008, Volume 13, Number 3, Page 321

Comments (0)

Please log in or register to comment.
Log in