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M404091200v1
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Papers In Press, published online ahead of print May 24, 2004
J. Biol. Chem, 10.1074/jbc.M404091200
Submitted on April 13, 2004
Revised on May 24, 2004
Accepted on May 24, 2004

The position of a key tyrosine in dTDP-4-keto-6-deoxy-D-glucose-5-epimerase (EvaD) alters the substrate profile for this RmlC-like enzyme

Alexandra B. Merkel, Louise L. Major, James C. Errey, Michael D. Burkart, Robert A. Field, Christopher T. Walsh, and James H. Naismith

Centre for Biomolecular Science, University of St. Andrews, St. Andrews, Scotland KY16 9ST

Corresponding Author: naismith{at}st-andrews.ac.uk

Vancomycin, the last line of defence antibiotic, depends upon the attachment of the carbohydrate vancosamine to an aglycone skeleton for antibacterial activity. Vancomycin is a naturally occurring secondary metabolite that can be produced by bacterial fermentation. To combat emerging resistance , it has been proposed to genetically engineer bacteria to produce analogues of vancomycin. This requires a detailed understanding of the biochemical steps in the synthesis of vancomycin. Here we report the 1.4Å structure and biochemical characterisation of EvaD, an RmlC-like protein, that is required for the C5 epimerisation during synthesis of dTDP-epivancosamine. EvaD, although clearly belonging to the RmlC class of enzymes, displays very low activity in the archetypal RmlC reaction (double epimerisation of dTDP-6-deoxy-4-keto-D-glucose at C3and C5). The high resolution structure of EvaD compared to the structures of authentic RmlC enzymes indicates that a subtle change in the enzyme active site repositions a key catalytic Tyr residue. A mutant designed to re-establish the normal position of the Tyr increases EvaD’s RmlC-like activity.


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