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

Journal Article · · ACS Chemical Biology
DOI:https://doi.org/10.1021/cb501042a· OSTI ID:1182773
 [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
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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).

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE; National Institutes of Health (NIH)
Grant/Contract Number:
AC02-06CH11357; S10 RR027109; DP2 OD008463
OSTI ID:
1182773
Journal Information:
ACS Chemical Biology, Vol. 10, Issue 5; ISSN 1554-8929
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 12 works
Citation information provided by
Web of Science

References (25)

Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature journal January 2013
Thiazole/oxazole-modified microcins: complex natural products from ribosomal templates journal June 2011
Plantazolicin A and B: Structure Elucidation of Ribosomally Synthesized Thiazole/Oxazole Peptides from Bacillus amyloliquefaciens FZB42 journal June 2011
Plantazolicin, a Novel Microcin B17/Streptolysin S-Like Natural Product from Bacillus amyloliquefaciens FZB42 journal January 2011
From Peptide Precursors to Oxazole and Thiazole-Containing Peptide Antibiotics: Microcin B17 Synthase journal November 1996
Structure Determination and Interception of Biosynthetic Intermediates for the Plantazolicin Class of Highly Discriminating Antibiotics journal October 2011
Marine Molecular Machines: Heterocyclization in Cyanobactin Biosynthesis journal June 2010
Cofactor Requirements and Reconstitution Of Microcin B17 Synthetase:  A Multienzyme Complex that Catalyzes the Formation of Oxazoles and Thiazoles in the Antibiotic Microcin B17 † journal April 1999
Structural and functional insight into an unexpectedly selective N-methyltransferase involved in plantazolicin biosynthesis journal July 2013
Bacillus anthracis journal March 2003
Biochemical and Structural Analysis of Substrate Promiscuity in Plant Mg2+-Dependent O-Methyltransferases journal April 2008
Characterization and structure of DhpI, a phosphonate O -methyltransferase involved in dehydrophos biosynthesis journal September 2010
RebG- and RebM-Catalyzed Indolocarbazole Diversification journal March 2006
Arg-Thz is a minimal substrate for the Nα,Nα-arginyl methyltransferase involved in the biosynthesis of plantazolicin journal January 2013
Synthesis of Plantazolicin Analogues Enables Dissection of Ligand Binding Interactions of a Highly Selective Methyltransferase journal September 2013
A Nucleosidase Required for In Vivo Function of the S-Adenosyl-L-Methionine Radical Enzyme, Biotin Synthase journal May 2005
Architectures, mechanisms and molecular evolution of natural product methyltransferases journal January 2012
Biosynthesis and Regulation of Grisemycin, a New Member of the Linaridin Family of Ribosomally Synthesized Peptides Produced by Streptomyces griseus IFO 13350 journal May 2011
Catalytic promiscuity of a bacterial α- N -methyltransferase journal July 2012
Engineering Unnatural Variants of Plantazolicin through Codon Reprogramming journal June 2013
Multiparametric scaling of diffraction intensities journal April 2003
Phaser crystallographic software journal July 2007
The Phenix software for automated determination of macromolecular structures journal September 2011
REFMAC 5 for the refinement of macromolecular crystal structures journal March 2011
AQUA and PROCHECK-NMR: Programs for checking the quality of protein structures solved by NMR journal December 1996

Cited By (3)

Structural, mechanistic and functional insight into gliotoxin bis -thiomethylation in Aspergillus fumigatus journal February 2017
The genomic landscape of ribosomal peptides containing thiazole and oxazole heterocycles journal October 2015
Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus text January 2017

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