Crystal structures of lipoglycopeptide antibiotic deacetylases: implications for the biosynthesis of A40926 and teicoplanin.
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Zou Y, Brunzelle JS, Nair SK
Crystal structures of lipoglycopeptide antibiotic deacetylases: implications for the biosynthesis of A40926 and teicoplanin.
Chem Biol. 2008 Jun;15(6):533-45. doi: 10.1016/j.chembiol.2008.05.009.
- PubMed ID
- 18559264 [ View in PubMed]
- Abstract
The lipoglycopeptide antibiotics teicoplanin and A40926 have proven efficacy against Gram-positive pathogens. These drugs are distinguished from glycopeptide antibiotics by N-linked long chain acyl-D-glucosamine decorations that contribute to antibacterial efficacy. During the biosynthesis of lipoglycopeptides, tailoring glycosyltransferases attach an N-acetyl-D-glucosamine to the aglycone, and this N-acetyl-glucosaminyl pseudoaglycone is deacetylated prior to long chain hydrocarbon attachment. Here we present several high-resolution crystal structures of the pseudoaglycone deacetylases from the biosynthetic pathways of teicoplanin and A40926. The cocrystal structure of the teicoplanin pseudoaglycone deacetylase with a fatty acid product provides further insights into the roles of active-site residues, and suggests mechanistic similarities with structurally distinct zinc deacetylases, such as peptidoglycan deacetylase and LpxC. A unique, structurally mobile capping lid, located at the apex of these pseudoaglycone deacetylases, likely serves as a determinant of substrate specificity.