Actions for Insights into Methyltransferase Specificity and Bioactivity of Derivatives of the Antibiotic Plantazolicin [electronic resource].

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Insights into Methyltransferase Specificity and Bioactivity of Derivatives of the Antibiotic Plantazolicin [electronic resource].

Published
Washington, D.C. : United States. Dept. of Energy, 2015.
Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy
Physical Description
pages 1,209-1,216 : digital, PDF file
Additional Creators
Argonne National Laboratory, United States. Department of Energy, National Institutes of Health (U.S.), and United States. Department of Energy. Office of Scientific and Technical Information
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Summary
Peptide antibiotics represent a class of conformationally-constrained natural products of growing pharmaceutical interest. Plantazolicin (PZN) is a linear, polyheterocyclic natural product with highly selective and potent activity against the anthrax-causing bacterium, Bacillus anthracis. The bioactivity of PZN is contingent on dimethylation of its N-terminal Arg residue by an S-adenosylmethionine-dependent methyltransferase. Here in this paper, we explore the substrate tolerances of two homologous PZN methyltransferases by carrying out kinetic analyses of the enzymes against a synthetic panel of truncated PZN analogs containing the N-terminal Arg residue. X-ray cocrystal structures of the PZN methyltransferases with each of these heterocycle-containing substrates provide a rationale for understanding the strict substrate specificity of these enzymes. Kinetic studies of structure-guided, site-specific variants allowed for the assignment of residues governing catalysis and substrate scope. Microbiological testing further revealed that upon dimethylation of the N-terminal Arg, a pentaheterocyclized PZN analog retained potent anti-B. anthracis activity, nearly equal to that of full-length PZN. These studies may be useful in the biosynthetic engineering of natural product analogs with different bioactivity profiles, as demonstrated by our identification of a truncated plantazolicin derivative that is active against methicillin-resistant Staphylococcus aureus (MRSA).
Report Numbers
E 1.99:1182773
Subject(s)
Note
Published through SciTech Connect.
01/30/2015.
ACS Chemical Biology 10 5 ISSN 1554-8929 AM
Yue Hao; Patricia M. Blair; Abhishek Sharma; Douglas A. Mitchell; Satish K. Nair.
Funding Information
AC02-06CH11357
S10 RR027109
DP2 OD008463
View MARC record | catkey: 23499822