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

J. Biol. Chem., Vol. 279, Issue 52, 54216-54220, December 24, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/52/54216    most recent M411177200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Song, E. S. Articles by Hersh, L. B. Search for Related Content PubMed PubMed Citation Articles by Song, E. S. Articles by Hersh, L. B. Social Bookmarking                      What's this?

ATP Effects on Insulin-degrading Enzyme Are Mediated Primarily through Its Triphosphate Moiety^*

Eun Suk Song, Maria Aparecida Juliano, Luiz Juliano, Michael G. Fried, Steven L. Wagner¶, and Louis B. Hersh||

From the Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0084, the Department of Biophysics, Escola Paulista de Medicina, Sao Paulo 04023-900, Brazil, and ^¶Neurogenetics Inc., La Jolla, California 92037

It has been reported previously that ATP inhibits the insulysin reaction (Camberos, M. C., Perez, A. A., Udrisar, D. P., Wanderley, M. I., and Cresto, J. C. (2001) Exp. Biol. Med. 226, 334–341). We report here that with 2-aminobenzoyl-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl as substrate, ATP and other nucleotides increase the rate >20-fold in Tris buffer. There is no specificity with respect to the nucleotide; however, ATP is more effective than ADP, which is more effective than AMP. Triphosphate itself was as effective as ATP, indicating it is this moiety that is responsible for activation. The binding of triphosphate was shown to be at a site distinct from the active site, thus acting as a noncompetitive activator. With the physiological substrates insulin and amyloid peptide, nucleotides and triphosphate were without effect. However, with small physiological peptides such as bradykinin and dynorphin B-9, ATP and triphosphate increased the rate of hydrolysis 10-fold. Triphosphate and ATP shifted the oligomeric state of the enzyme from primarily dimer-tetramers to a monomer. These data suggest the presence of an allosteric regulatory site on insulysin that may shift its specificity toward small peptide substrates.

Received for publication, September 29, 2004

^* This work was supported in part by National Institute on Drug Abuse Grant DA02243 (to L. B. H.), the NIA, National Institutes of Health Grant AG19323 (to L. B. H.), the NIDDK, National Institutes of Health Grant DK54289 (to M. G. F.), the Alzheimer's Association (to L. B. H.), and by Fundação de Amparo Pesquisa do Estado de São Paulo FAPESP (to L. J.), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (to L. J.), and Human Frontiers for Science Progress Grant RG 00043/2000-M (to L. J.). 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.

^|| To whom correspondence should be addressed: Dept. of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, 800 Rose St., Lexington, KY 40536-0084. Tel.: 859-323-5549; Fax: 859-323-1727; E-mail: lhersh{at}uky.edu.

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

This article has been cited by other articles:

				H. Im, M. Manolopoulou, E. Malito, Y. Shen, J. Zhao, M. Neant-Fery, C.-Y. Sun, S. C. Meredith, S. S. Sisodia, M. A. Leissring, et al. Structure of Substrate-free Human Insulin-degrading Enzyme (IDE) and Biophysical Analysis of ATP-induced Conformational Switch of IDE J. Biol. Chem., August 31, 2007; 282(35): 25453 - 25463. [Abstract] [Full Text] [PDF]

				M. Kim, L. B. Hersh, M. A. Leissring, M. Ingelsson, T. Matsui, W. Farris, A. Lu, B. T. Hyman, D. J. Selkoe, L. Bertram, et al. Decreased Catalytic Activity of the Insulin-degrading Enzyme in Chromosome 10-Linked Alzheimer Disease Families J. Biol. Chem., March 16, 2007; 282(11): 7825 - 7832. [Abstract] [Full Text] [PDF]

				M. del Carmen Camberos and J. C. Cresto Insulin-Degrading Enzyme Hydrolyzes ATP Experimental Biology and Medicine, February 1, 2007; 232(2): 281 - 292. [Abstract] [Full Text] [PDF]

				E. S. Song, A. Daily, M. G. Fried, M. A. Juliano, L. Juliano, and L. B. Hersh Mutation of Active Site Residues of Insulin-degrading Enzyme Alters Allosteric Interactions J. Biol. Chem., May 6, 2005; 280(18): 17701 - 17706. [Abstract] [Full Text] [PDF]