HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 51, 36829-36836, December 21, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/51/36829    most recent M707002200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Iben, L. G. Articles by Toyn, J. H. Search for Related Content PubMed PubMed Citation Articles by Iben, L. G. Articles by Toyn, J. H. Social Bookmarking                      What's this?

Signal Peptide Peptidase and -Secretase Share Equivalent Inhibitor Binding Pharmacology^*

Lawrence G. Iben, Richard E. Olson, Lynn A. Balanda, Sukhanya Jayachandra, Barbara J. Robertson, Vanessa Hay^¶, John Corradi, C. V. C. Prasad, Robert Zaczek, Charles F. Albright, and Jeremy H. Toyn¹

From the Departments of Neuroscience Drug Discovery and Applied Biotechnology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492 and the ^¶Department of Applied Biotechnology, Bristol-Myers Squibb Research and Development, Pennington, New Jersey 08534

The enzyme -secretase has long been considered a potential pharmaceutical target for Alzheimer disease. Presenilin (the catalytic subunit of -secretase) and signal peptide peptidase (SPP) are related transmembrane aspartyl proteases that cleave transmembrane substrates. SPP and -secretase are pharmacologically similar in that they are targeted by many of the same small molecules, including transition state analogs, non-transition state inhibitors, and amyloid β-peptide modulators. One difference between presenilin and SPP is that the proteolytic activity of presenilin functions only within a multisubunit complex, whereas SPP requires no additional protein cofactors for activity. In this study, -secretase inhibitor radioligands were used to evaluate SPP and -secretase inhibitor binding pharmacology. We found that the SPP enzyme exhibited distinct binding sites for transition state analogs, non-transition state inhibitors, and the nonsteroidal anti-inflammatory drug sulindac sulfide, analogous to those reported previously for -secretase. In the course of this study, cultured cells were found to contain an abundance of SPP binding activity, most likely contributed by several of the SPP family proteins. The number of SPP binding sites was in excess of -secretase binding sites, making it essential to use selective radioligands for evaluation of -secretase binding under these conditions. This study provides further support for the idea that SPP is a useful model of inhibitory mechanisms and structure in the SPP/presenilin protein family.

Received for publication, August 21, 2007 , and in revised form, October 5, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492. Tel.: 203-677-7511; Fax: 203-677-7569; E-mail: jeremy.toyn{at}bms.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Fluhrer, H. Steiner, and C. Haass Intramembrane Proteolysis by Signal Peptide Peptidases: A Comparative Discussion of GXGD-type Aspartyl Proteases J. Biol. Chem., May 22, 2009; 284(21): 13975 - 13979. [Abstract] [Full Text] [PDF]

				E. Futai, S. Yagishita, and S. Ishiura Nicastrin Is Dispensable for {gamma}-Secretase Protease Activity in the Presence of Specific Presenilin Mutations J. Biol. Chem., May 8, 2009; 284(19): 13013 - 13022. [Abstract] [Full Text] [PDF]

				C. R. Burton, J. E. Meredith, D. M. Barten, M. E. Goldstein, C. M. Krause, C. J. Kieras, L. Sisk, L. G. Iben, C. Polson, M. W. Thompson, et al. The Amyloid-{beta} Rise and {gamma}-Secretase Inhibitor Potency Depend on the Level of Substrate Expression J. Biol. Chem., August 22, 2008; 283(34): 22992 - 23003. [Abstract] [Full Text] [PDF]

				A. Tolia, K. Horre, and B. De Strooper Transmembrane Domain 9 of Presenilin Determines the Dynamic Conformation of the Catalytic Site of {gamma}-Secretase J. Biol. Chem., July 11, 2008; 283(28): 19793 - 19803. [Abstract] [Full Text] [PDF]