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Papers In Press, published online ahead of print April 27, 2005
Unité de Chimie Biologique, UMR 206, INRA, Thiverval-Grignon 78850
Corresponding Author: briozzo{at}lebs.cnrs-gif.fr
Bacterial UMP kinases are essential enzymes involved in the multistep synthesis of nucleoside triphosphates. They are hexamers regulated by the allosteric activator GTP, and inhibited by UTP. We solved the crystal structure of Escherichia coli UMP kinase bound either to the UMP substrate (2.3 Å resolution), the UDP product (2.6 Å), or UTP (2.45 Å). The monomer fold, unrelated to that of other NMP kinases, belongs to the carbamate kinase-like superfamily. However the phosphate acceptor binding cleft and subunit assembly are characteristic of UMP kinase. Interactions with UMP explain the high specificity for this natural substrate. UTP, previously described as an allosteric inhibitor, was unexpectedly found in the phosphate acceptor site, suggesting that it acts as a competitive inhibitor. Site-directed mutagenesis of residues T138 and N140, involved in both uracil recognition and active sites interaction within the hexamer, decreased the activation by GTP and inhibition by UTP. These experiments suggest a cross-talk mechanism between enzyme subunits involved in cooperative binding at the phosphate acceptor site and in allosteric regulation by GTP. As bacterial UMP kinases have no counterpart in eukaryotes, the information provided here could help the design of new antibiotics.
J. Biol. Chem, 10.1074/jbc.M501849200
Submitted on February 18, 2005
Revised on March 30, 2005
Accepted on April 27, 2005
Structure of Escherichia coli UMP kinase differs from that of other NMP kinases and sheds new light on enzyme regulation
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