Crystal structure of the N-acetylmuramic acid {alpha}-1-phosphate (MurNAc-{alpha}1P) uridylytransferase MurU, a minimal sugar-nucleotidyltransferase and potential drug target enzyme in Gram-negative pathogens [Enzymology]

March 12th, 2015 by Renner-Schneck, M., Hinderberger, I., Gisin, J., Exner, T., Mayer, C., Stehle, T.

The N-acetylmuramic acid α-1-phosphate (MurNAc-α1P) uridylyltransferase MurU catalyzes the synthesis of uridine diphosphate (UDP)-MurNAc, a crucial precursor of the bacterial peptidoglycan cell wall. MurU is part of a recently identified cell wall recycling pathway in Gram-negative bacteria that bypasses the general de-novo biosynthesis of UDP-MurNAc and contributes to high intrinsic resistance to the antibiotic fosfomycin, which targets UDP-MurNAc de novo biosynthesis. To provide insights into substrate binding and specificity, we solved crystal structures of MurU of Pseudomonas putida in native and ligand-bound states at high resolution. With the help of these structures, critical enzyme- substrate interactions were identified that enable tight binding of MurNAc-α1P to the active site of MurU. The MurU structures define a "minimal domain" required for general nucleotidyltransferase activity. They furthermore provide a structural basis for the chemical design of inhibitors of MurU, which could serve as novel drugs in combination therapy against multi-resistant Gram-negative pathogens.
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