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

This Article Full Text Full Text (PDF) 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 Google Scholar Google Scholar Articles by Mourey, L. Articles by Samama, J.-P. Search for Related Content PubMed PubMed Citation Articles by Mourey, L. Articles by Samama, J.-P. Social Bookmarking                      What's this?

J Biol Chem, Vol. 274, Issue 36, 25260-25265, September 3, 1999

Inhibition of the Broad Spectrum Nonmetallocarbapenamase of Class A (NMC-A) -Lactamase from Enterobacter cloacae by Monocyclic -Lactams^,

Lionel Mourey, Lakshmi P. Kotra^¶, John Bellettini, Alexey Bulychev^¶, Michael O'Brien, Marvin J. Miller, Shahriar Mobashery^¶, and Jean-Pierre Samama

From the  Groupe de Cristallographie Biologique, Institut de Pharmacologie et de Biologie Structurale du CNRS, 205 Route de Narbonne, 31077 Toulouse Cedex, France, the ^¶ Department of Chemistry, Wayne State University, Detroit, Michigan 48202, and the  Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556

-Lactamases hydrolyze -lactam antibiotics, a reaction that destroys their antibacterial activity. These enzymes, of which four classes are known, are the primary cause of resistance to -lactam antibiotics. The class A -lactamases form the largest group. A novel class A -lactamase, named the nonmetallocarbapenamase of class A (NMC-A) -lactamase, has been discovered recently that has a broad substrate profile that included carbapenem antibiotics. This is a serious development, since carbapenems have been relatively immune to the action of these resistance enzymes. Inhibitors for this enzyme are sought. We describe herein that a type of monobactam molecule of our design inactivates the NMC-A -lactamase rapidly, efficiently, and irreversibly. The mechanism of inactivation was investigated by solving the x-ray structure of the inhibited NMC-A enzyme to 1.95 Å resolution. The structure shed light on the nature of the fragmentation of the inhibitor on enzyme acylation and indicated that there are two acyl-enzyme species that account for enzyme inhibition. Each of these inhibited enzyme species is trapped in a distinct local energy minimum that does not predispose the inhibitor species for deacylation, accounting for the irreversible mode of enzyme inhibition. Molecular dynamics simulations provided evidence in favor of a dynamic motion for the acyl-enzyme species, which samples a considerable conformational space prior to the entrapment of the two stable acyl-enzyme species in the local energy minima. A discussion of the likelihood of such dynamic motion for turnover of substrates during the normal catalytic processes of the enzyme is presented.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati