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EMBO reports 9, 2, 199–205 (2008)
doi:10.1038/sj.embor.7401154
AOP Published online: 11 January 2008
A structural basis for the allosteric regulation of non-hydrolysing UDP-GlcNAc 2-epimerases
Lucas M Velloso1*, Shyam S Bhaskaran1*, Raymond Schuch2, Vincent A Fischetti2 & C Erec Stebbins1
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1 Laboratory of Structural Microbiology and,
2 Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA
To whom correspondence should be addressed
C Erec Stebbins Tel: +1 212 327 7190; Fax: +1 212 327 7191; E-mail: stebbins@rockefeller.edu
* These authors contributed equally to this work
Received 19 June 2007; Accepted 19 November 2007; Published online 11 January 2008.
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Abstract
The non-hydrolysing bacterial UDP-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase) catalyses the conversion of UDP-GlcNAc into UDP-N-acetylmannosamine, an intermediate in the biosynthesis of several cell-surface polysaccharides. This enzyme is allosterically regulated by its substrate UDP-GlcNAc. The structure of the ternary complex between the Bacillus anthracis UDP-GlcNAc 2-epimerase, its substrate UDP-GlcNAc and the reaction intermediate UDP, showed direct interactions between UDP and its substrate, and between the complex and highly conserved enzyme residues, identifying the allosteric site of the enzyme. The binding of UDP-GlcNAc is associated with conformational changes in the active site of the enzyme. Kinetic data and mutagenesis of the highly conserved UDP-GlcNAc-interacting residues confirm their importance in the substrate binding and catalysis of the enzyme. This constitutes the first example to our knowledge, of an enzymatic allosteric activation by direct interaction between the substrate and the allosteric activator.
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