Crystal structures of lipoglycopeptide antibiotic deacetylases: implications for the biosynthesis of A40926 and teicoplanin.
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.
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Yaozhong
Y
Zou
Joseph S
JS
Brunzelle
Satish K
SK
Nair
D000192:Actinomycetales / Q000201:enzymology*; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D017334:Teicoplanin / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D015032:Zinc / Q000494:pharmacology
C054981:A 40926; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D017334:Teicoplanin; D006867:Hydrolases; D015032:Zinc