Jump to ContentJump to Main Navigation

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

12 Issues per year


IMPACT FACTOR increased in 2014: 3.268
Rank 106 out of 289 in category Biochemistry & Molecular Biology in the 2014 Thomson Reuters Journal Citation Report/Science Edition

SCImago Journal Rank (SJR) 2014: 1.596
Source Normalized Impact per Paper (SNIP) 2014: 0.845
Impact per Publication (IPP) 2014: 2.992

VolumeIssuePage

Issues

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

Siying Ye1 / Siew Yeen Chai2 / Rebecca A. Lew3 / Anthony L. Albiston4

1.

2.

3.

4.

Corresponding author

Citation Information: Biological Chemistry. Volume 388, Issue 4, Pages 399–403, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2007.044, March 2007

Publication History

Received:
October 18, 2006
Accepted:
January 9, 2007
Published Online:
2007-03-28

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

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]
Hanna Andersson and Mathias Hallberg
International Journal of Hypertension, 2012, Volume 2012, Page 1
[2]
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]
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
[5]
Harald John, Stefanie John, and Wolf‐Georg Forssmann
Journal of Peptide Science, 2008, Volume 14, Number 7, Page 797
[6]
Masafumi Tsujimoto, Yoshikuni Goto, Masato Maruyama, and Akira Hattori
Heart Failure Reviews, 2008, Volume 13, Number 3, Page 285

Comments (0)

Please log in or register to comment.