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

J. Biol. Chem., Vol. 280, Issue 14, 14070-14075, April 8, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/14/14070    most recent M414412200v1 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 Eschenburg, S. Articles by Schönbrunn, E. Search for Related Content PubMed PubMed Citation Articles by Eschenburg, S. Articles by Schönbrunn, E. Social Bookmarking                      What's this?

A Novel Inhibitor That Suspends the Induced Fit Mechanism of UDP-N-acetylglucosamine Enolpyruvyl Transferase (MurA)^*

Susanne Eschenburg, Melanie A. Priestman, Farid A. Abdul-Latif¶, Carole Delachaume||, Florence Fassy**, and Ernst Schönbrunn

From the Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, Department of Structural Biology, Max-Planck Institute for Molecular Physiology, 44227 Dortmund, Germany, ^**Aventis Pharma, 94403 Vitry sur Seine Cedex, France, ^||Novexel, 93320 Romainville, France, and ^¶Aventis Pharma, Combinatorial Technologies Center, Tucson, Arizona 85737

MurA (UDP-N-acetylglucosamine enolpyruvyl transferase, EC 2.5.1.7) catalyzes the first committed step in the synthesis of the bacterial cell wall. It is the target of the naturally occurring, broad-spectrum antibiotic fosfomycin. Fosfomycin, an epoxide, is a relatively poor drug because an ever-increasing number of bacteria have developed resistance to fosfomycin. Thus, there is a critical need for the development of novel drugs that target MurA by a different molecular mode of action. We have identified a new scaffold of potent MurA inhibitors, derivatives of 5-sulfonoxy-anthranilic acid, using high-throughput screening. T6361 and T6362 are competitive inhibitors of MurA with respect to the first substrate, UDP-N-acetylglucosamine (UNAG), with a K_i of 16 µM. The crystal structure of the MurA·T6361 complex at 2.6 Å resolution, together with fluorescence data, revealed that the inhibitor targets a loop, Pro¹¹² to Pro¹²¹, that is crucial for the structural changes of the enzyme during catalysis. Thus, this new class of MurA inhibitors is not active site-directed but instead obstructs the transition from the open (unliganded) to the closed (UNAG-liganded) enzyme form. The results provide evidence for the existence of a MurA·UNAG collision complex that may be specifically targeted by small molecules different from ground-state analogs of the enzymatic reaction.

Received for publication, December 22, 2004 , and in revised form, February 3, 2005.

The atomic coordinates and structure factors (code 1YBG) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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.

The on-line version of this article (available at http://ww.jbc.org) contains supplemental data and supplemental Figs. S1 and S2.

To whom correspondence should be addressed: Dept. of Medicinal Chemistry, University of Kansas, 4040a Malott Hall, Lawrence, KS 66045. Tel.: 785-864-4503; E-mail: eschoenb{at}ku.edu.

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

This article has been cited by other articles:

				Y. Yang, A. Severin, R. Chopra, G. Krishnamurthy, G. Singh, W. Hu, D. Keeney, K. Svenson, P. J. Petersen, P. Labthavikul, et al. 3,5-Dioxopyrazolidines, Novel Inhibitors of UDP-N- Acetylenolpyruvylglucosamine Reductase (MurB) with Activity against Gram-Positive Bacteria Antimicrob. Agents Chemother., February 1, 2006; 50(2): 556 - 564. [Abstract] [Full Text] [PDF]