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J. Biol. Chem., Vol. 280, Issue 13, 13055-13061, April 1, 2005

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The Role of the Novel Fem Protein VanK in Vancomycin Resistance in Streptomyces coelicolor^*

Hee-Jeon Hong¶, Matthew I. Hutchings, Lionel M. Hill||, and Mark J. Buttner

From the Departments of Molecular Microbiology and ^||Metabolic Biology, John Innes Centre, Colney, Norwich NR4 7UH, United Kingdom

The non-pathogenic, non-glycopeptide-producing actinomycete Streptomyces coelicolor carries a cluster of seven genes (vanSRJKHAX) that confers inducible, high level resistance to vancomycin. The vanK gene has no counterpart in previously characterized vancomycin resistance clusters, yet vanK is required for vancomycin resistance in S. coelicolor. VanK belongs to the Fem family of enzymes, which add the branch amino acid(s) to the stem pentapeptide of peptidoglycan precursors. Upon exposure to vancomycin, the VanRS two-component system switches on expression of all seven van genes, and the VanHAX enzymes reprogram the cell wall such that precursors terminate D-Ala-D-lactate (Lac) rather than D-Ala-D-Ala, thus conferring resistance to vancomycin, which only binds D-Ala-D-Ala-containing precursors. Here we provide biochemical and genetic evidence that VanK is required for vancomycin resistance because the constitutively expressed FemX enzyme, encoded elsewhere on the chromosome, cannot recognize D-Lac-containing precursors as a substrate, whereas VanK can. Consistent with this view, D-Lac-containing precursors carrying the Gly branch are present in the wild type transiently exposed to vancomycin but are undetectable in a vanK mutant treated in the same way. Further, femX null mutants are viable in the presence of vancomycin but die in its absence. Because only VanK can recognize D-Lac-containing precursors, vancomycin-induced expression of VanHAX in a vanK mutant is lethal, and so vanK is required for vancomycin resistance.

Received for publication, December 8, 2004

^* This work was funded by Biotechnology and Biological Sciences Research Council Grant 208/P20040 (to H-J. H. and M. J. B.) and by a grant-in-aid to the John Innes Centre from the BBSRC. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These two authors contributed equally to this work.

^¶ To whom correspondence should be addressed: Dept. of Molecular Microbiology, John Innes Centre, Colney, Norwich NR4 7UH, UK. Tel.: 44-1603-450757; Fax: 44-1603-450778; E-mail: Hong{at}bbsrc.ac.uk.

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