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Title: The structural basis of N-acyl-$α$-amino-β-lactone formation catalyzed by a nonribosomal peptide synthetase

Abstract

Nonribosomal peptide synthetases produce diverse natural products using a multidomain architecture where the growing peptide, attached to an integrated carrier domain, is delivered to neighboring catalytic domains for bond formation and modification. Investigation of these systems can lead to the discovery of new structures, unusual biosynthetic transformations, and to the engineering of catalysts for generating new products. The antimicrobial β-lactone obafluorin is produced nonribosomally from dihydroxybenzoic acid and a β-hydroxy amino acid that cyclizes into the β-lactone during product release. Here we report the structure of the nonribosomal peptide synthetase ObiF1, highlighting the structure of the β-lactone-producing thioesterase domain and an interaction between the C-terminal MbtH-like domain with an upstream adenylation domain. Biochemical assays examine catalytic promiscuity, provide mechanistic insight, and demonstrate utility for generating obafluorin analogs. These results advance our understanding of the structural cycle of nonribosomal peptide synthetases and provide insights into the production of β-lactone natural products.

Authors:
ORCiD logo [1]; ORCiD logo [2];  [2]; ORCiD logo [2]; ORCiD logo [1]
  1. Univ. at Buffalo, NY (United States)
  2. Washington Univ., St. Louis, MO (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
Research Corporation for Science Advancement; Alfred P. Sloan Foundation; National Science Foundation (NSF); National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); National Cancer Institute (NCI); USDOE Office of Science (SC)
OSTI Identifier:
1545877
Grant/Contract Number:  
[DBI-0521250; GM116957; AC02-06CH11357; 1S10OD012289-01A1]
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
[ Journal Volume: 10; Journal Issue: 1]; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Natural products; X-ray crystallography

Citation Formats

Kreitler, Dale F., Gemmell, Erin M., Schaffer, Jason E., Wencewicz, Timothy A., and Gulick, Andrew M. The structural basis of N-acyl-$α$-amino-β-lactone formation catalyzed by a nonribosomal peptide synthetase. United States: N. p., 2019. Web. doi:10.1038/s41467-019-11383-7.
Kreitler, Dale F., Gemmell, Erin M., Schaffer, Jason E., Wencewicz, Timothy A., & Gulick, Andrew M. The structural basis of N-acyl-$α$-amino-β-lactone formation catalyzed by a nonribosomal peptide synthetase. United States. doi:10.1038/s41467-019-11383-7.
Kreitler, Dale F., Gemmell, Erin M., Schaffer, Jason E., Wencewicz, Timothy A., and Gulick, Andrew M. Wed . "The structural basis of N-acyl-$α$-amino-β-lactone formation catalyzed by a nonribosomal peptide synthetase". United States. doi:10.1038/s41467-019-11383-7. https://www.osti.gov/servlets/purl/1545877.
@article{osti_1545877,
title = {The structural basis of N-acyl-$α$-amino-β-lactone formation catalyzed by a nonribosomal peptide synthetase},
author = {Kreitler, Dale F. and Gemmell, Erin M. and Schaffer, Jason E. and Wencewicz, Timothy A. and Gulick, Andrew M.},
abstractNote = {Nonribosomal peptide synthetases produce diverse natural products using a multidomain architecture where the growing peptide, attached to an integrated carrier domain, is delivered to neighboring catalytic domains for bond formation and modification. Investigation of these systems can lead to the discovery of new structures, unusual biosynthetic transformations, and to the engineering of catalysts for generating new products. The antimicrobial β-lactone obafluorin is produced nonribosomally from dihydroxybenzoic acid and a β-hydroxy amino acid that cyclizes into the β-lactone during product release. Here we report the structure of the nonribosomal peptide synthetase ObiF1, highlighting the structure of the β-lactone-producing thioesterase domain and an interaction between the C-terminal MbtH-like domain with an upstream adenylation domain. Biochemical assays examine catalytic promiscuity, provide mechanistic insight, and demonstrate utility for generating obafluorin analogs. These results advance our understanding of the structural cycle of nonribosomal peptide synthetases and provide insights into the production of β-lactone natural products.},
doi = {10.1038/s41467-019-11383-7},
journal = {Nature Communications},
number = [1],
volume = [10],
place = {United States},
year = {2019},
month = {7}
}

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