Open AccessStructure of MurA (UDP‐ N ‐acetylglucosamine enolpyruvyl transferase) from Vibrio fischeri in complex with substrate UDP‐ N ‐acetylglucosamine and the drug fosfomycin
Author(s) -
Bensen D. C.,
Rodriguez S.,
Nix J.,
Cunningham M. L.,
Tari L. W.
Publication year - 2012
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
ISSN - 1744-3091
DOI - 10.1107/s1744309112006720
Subject(s) - fosfomycin , mura , transferase , acetylglucosamine , biology , ferredoxin , biochemistry , enzyme , antibiotics , liquid crystal display , computer science , operating system
The development of new antibiotics is necessitated by the rapid development of resistance to current therapies. UDP‐ N ‐acetylglucosamine enolpyruvyl transferase (MurA), which catalyzes the first committed step of bacterial peptidoglycan biosynthesis, is a prime candidate for therapeutic intervention. MurA is the target of the antibiotic fosfomycin, a natural product produced by Streptomyces . Despite possessing a high degree of sequence conservation with MurA enzymes from fosfomycin‐susceptible organisms, recent microbiological studies suggest that MurA from Vibrio fischeri (VfiMurA) may confer fosfomycin resistance via a mechanism that is not yet understood. The crystal structure of VfiMurA in a ternary complex with the substrate UDP‐ N ‐acetylglucosamine (UNAG) and fosfomycin has been solved to a resolution of 1.93 Å. Fosfomycin is known to inhibit MurA by covalently binding to a highly conserved cysteine in the active site of the enzyme. A comparison of the title structure with the structure of fosfomycin‐susceptible Haemophilus influenzae MurA (PDB entry 2rl2 ) revealed strikingly similar conformations of the mobile substrate‐binding loop and clear electron density for a fosfomycin–cysteine adduct. Based on these results, there are no distinguishing sequence/structural features in VfiMurA that would translate to a diminished sensitivity to fosfomycin. However, VfiMurA is a robust crystallizer and shares high sequence identity with many clinically relevant bacterial pathogens. Thus, it would serve as an ideal system for use in the structure‐guided optimization of new antibacterial agents.