PMID:15701635
| Citation |
Eschenburg, S, Priestman, MA, Abdul-Latif, FA, Delachaume, C, Fassy, F and Schönbrunn, E (2005) A novel inhibitor that suspends the induced fit mechanism of UDP-N-acetylglucosamine enolpyruvyl transferase (MurA). J. Biol. Chem. 280:14070-5 |
|---|---|
| Abstract |
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 microM. The crystal structure of the MurA.T6361 complex at 2.6 angstrom 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. |
| Links |
PubMed Online version:10.1074/jbc.M414412200 |
| Keywords |
Alkyl and Aryl Transferases/antagonists & inhibitors; Alkyl and Aryl Transferases/chemistry; Alkyl and Aryl Transferases/metabolism; Anti-Bacterial Agents/metabolism; Aspartic Acid/analogs & derivatives; Aspartic Acid/chemistry; Aspartic Acid/metabolism; Bacterial Proteins/chemistry; Bacterial Proteins/metabolism; Crystallography, X-Ray; Drug Resistance, Microbial; Enterobacter cloacae/enzymology; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/metabolism; Fosfomycin/metabolism; Macromolecular Substances; Models, Molecular; Molecular Structure; Naphthalenesulfonates/chemistry; Naphthalenesulfonates/metabolism; Protein Structure, Tertiary |
| edit table |
Significance
You can help EcoliWiki by summarizing why this paper is useful
Useful Materials and Methods
You can help Ecoliwiki by describing the useful materials (strains, plasmids, antibodies, etc) described in this paper.
Annotations
<annotationlinks/>
EcoliWiki Links
Add links to pages that link here (e.g. gene, product, method pages)
References
See Help:References for how to manage references in EcoliWiki.