TY - JOUR
T1 - Crystal Structures of Lipoglycopeptide Antibiotic Deacetylases
T2 - Implications for the Biosynthesis of A40926 and Teicoplanin
AU - Zou, Yaozhong
AU - Brunzelle, Joseph S.
AU - Nair, Satish K.
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2008/6/23
Y1 - 2008/6/23
N2 - 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.
AB - 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.
KW - CHEMBIO
KW - MICROBIO
KW - PROTEINS
UR - http://www.scopus.com/inward/record.url?scp=44949250886&partnerID=8YFLogxK
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U2 - 10.1016/j.chembiol.2008.05.009
DO - 10.1016/j.chembiol.2008.05.009
M3 - Article
C2 - 18559264
AN - SCOPUS:44949250886
VL - 15
SP - 533
EP - 545
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 6
ER -