Crystal Structures of Lipoglycopeptide Antibiotic Deacetylases: Implications for the Biosynthesis of A40926 and Teicoplanin

Yaozhong Zou, Joseph S. Brunzelle, Satish K. Nair

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)533-545
Number of pages13
JournalChemistry and Biology
Volume15
Issue number6
DOIs
StatePublished - Jun 23 2008

Keywords

  • CHEMBIO
  • MICROBIO
  • PROTEINS

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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