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Title: Insights into Methyltransferase Specificity and Bioactivity of Derivatives of the Antibiotic Plantazolicin

Abstract

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).

Authors:
 [1];  [2];  [2];  [3];  [4]
  1. Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Biochemistry
  2. Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Chemistry
  3. Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Chemistry; Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Microbiology; Univ. of Illinois, Urbana-Champaign, IL (United States). Inst. for Genomic Biology
  4. Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Biochemistry; Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Chemistry; Univ. of Illinois, Urbana-Champaign, IL (United States). Inst. for Genomic Biology; Univ. of Illinois, Urbana-Champaign, IL (United States). Center for Biophysics and Computational Biology
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1182773
Grant/Contract Number:  
AC02-06CH11357; S10 RR027109; DP2 OD008463
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
ACS Chemical Biology
Additional Journal Information:
Journal Volume: 10; Journal Issue: 5; Journal ID: ISSN 1554-8929
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Hao, Yue, Blair, Patricia M., Sharma, Abhishek, Mitchell, Douglas A., and Nair, Satish K. Insights into Methyltransferase Specificity and Bioactivity of Derivatives of the Antibiotic Plantazolicin. United States: N. p., 2015. Web. doi:10.1021/cb501042a.
Hao, Yue, Blair, Patricia M., Sharma, Abhishek, Mitchell, Douglas A., & Nair, Satish K. Insights into Methyltransferase Specificity and Bioactivity of Derivatives of the Antibiotic Plantazolicin. United States. doi:10.1021/cb501042a.
Hao, Yue, Blair, Patricia M., Sharma, Abhishek, Mitchell, Douglas A., and Nair, Satish K. Fri . "Insights into Methyltransferase Specificity and Bioactivity of Derivatives of the Antibiotic Plantazolicin". United States. doi:10.1021/cb501042a. https://www.osti.gov/servlets/purl/1182773.
@article{osti_1182773,
title = {Insights into Methyltransferase Specificity and Bioactivity of Derivatives of the Antibiotic Plantazolicin},
author = {Hao, Yue and Blair, Patricia M. and Sharma, Abhishek and Mitchell, Douglas A. and Nair, Satish K.},
abstractNote = {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).},
doi = {10.1021/cb501042a},
journal = {ACS Chemical Biology},
number = 5,
volume = 10,
place = {United States},
year = {Fri Jan 30 00:00:00 EST 2015},
month = {Fri Jan 30 00:00:00 EST 2015}
}

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