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:
-
[1];
[2];
[2];
[1]
- Univ. at Buffalo, NY (United States)
- 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:https://doi.org/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:https://doi.org/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}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 3 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Crystal Structure of the Termination Module of a Nonribosomal Peptide Synthetase
journal, August 2008
- Tanovic, A.; Samel, S. A.; Essen, L. -O.
- Science, Vol. 321, Issue 5889
An Antibacterial β-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis
journal, December 2017
- Lehmann, Johannes; Cheng, Tan-Yun; Aggarwal, Anup
- Angewandte Chemie International Edition, Vol. 57, Issue 1
Function of MbtH homologs in nonribosomal peptide biosynthesis and applications in secondary metabolite discovery
journal, August 2011
- Baltz, Richard H.
- Journal of Industrial Microbiology & Biotechnology, Vol. 38, Issue 11
Effects of deletions of mbtH-like genes on clorobiocin biosynthesis in Streptomyces coelicolor
journal, May 2007
- Wolpert, M.; Gust, B.; Kammerer, B.
- Microbiology, Vol. 153, Issue 5
Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica
journal, June 2007
- Udwary, D. W.; Zeigler, L.; Asolkar, R. N.
- Proceedings of the National Academy of Sciences, Vol. 104, Issue 25
Nonribosomal Peptide Synthesis-Principles and Prospects
journal, March 2017
- Süssmuth, Roderich D.; Mainz, Andi
- Angewandte Chemie International Edition, Vol. 56, Issue 14
Structures of two distinct conformations of holo-non-ribosomal peptide synthetases
journal, January 2016
- Drake, Eric J.; Miller, Bradley R.; Shi, Ce
- Nature, Vol. 529, Issue 7585
Using MbtH-Like Proteins to Alter the Substrate Profile of a Nonribosomal Peptide Adenylation Enzyme
journal, October 2018
- Mori, Shogo; Green, Keith D.; Choi, Ryan
- ChemBioChem, Vol. 19, Issue 20
Structure of the adenylation domain Thr1 involved in the biosynthesis of 4-chlorothreonine in Streptomyces sp. OH-5093-protein flexibility and molecular bases of substrate specificity
journal, August 2017
- Scaglione, Antonella; Fullone, Maria Rosaria; Montemiglio, Linda Celeste
- The FEBS Journal, Vol. 284, Issue 18
Biosynthesis and chemical diversity of β-lactone natural products
journal, January 2019
- Robinson, Serina L.; Christenson, James K.; Wackett, Lawrence P.
- Natural Product Reports, Vol. 36, Issue 3
Structural basis of nonribosomal peptide macrocyclization in fungi
journal, October 2016
- Zhang, Jinru; Liu, Nicholas; Cacho, Ralph A.
- Nature Chemical Biology, Vol. 12, Issue 12
Structure and Functional Analysis of RifR, the Type II Thioesterase from the Rifamycin Biosynthetic Pathway
journal, December 2008
- Claxton, Heather B.; Akey, David L.; Silver, Monica K.
- Journal of Biological Chemistry, Vol. 284, Issue 8
A Single Active Site Mutation in the Pikromycin Thioesterase Generates a More Effective Macrocyclization Catalyst
journal, August 2017
- Koch, Aaron A.; Hansen, Douglas A.; Shende, Vikram V.
- Journal of the American Chemical Society, Vol. 139, Issue 38
Trapping biosynthetic acyl-enzyme intermediates with encoded 2,3-diaminopropionic acid
journal, December 2018
- Huguenin-Dezot, Nicolas; Alonzo, Diego A.; Heberlig, Graham W.
- Nature, Vol. 565, Issue 7737
Conformational Dynamics in the Acyl-CoA Synthetases, Adenylation Domains of Non-ribosomal Peptide Synthetases, and Firefly Luciferase
journal, October 2009
- Gulick, Andrew M.
- ACS Chemical Biology, Vol. 4, Issue 10, p. 811-827
Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2)
journal, May 2002
- Bentley, S. D.; Chater, K. F.; Cerdeño-Tárraga, A. -M.
- Nature, Vol. 417, Issue 6885
Combining the polymerase incomplete primer extension method for cloning and mutagenesis with microscreening to accelerate structural genomics efforts
journal, January 2008
- Klock, Heath E.; Koesema, Eric J.; Knuth, Mark W.
- Proteins: Structure, Function, and Bioinformatics, Vol. 71, Issue 2
Nonribosomal Peptide Synthetases Involved in the Production of Medically Relevant Natural Products
journal, January 2008
- Felnagle, Elizabeth A.; Jackson, Emily E.; Chan, Yolande A.
- Molecular Pharmaceutics, Vol. 5, Issue 2
Structural insight into the necessary conformational changes of modular nonribosomal peptide synthetases
journal, December 2016
- Gulick, Andrew M.
- Current Opinion in Chemical Biology, Vol. 35
New Structural Data Reveal the Motion of Carrier Proteins in Nonribosomal Peptide Synthesis
journal, July 2016
- Kittilä, Tiia; Mollo, Aurelio; Charkoudian, Louise K.
- Angewandte Chemie International Edition, Vol. 55, Issue 34
An Orphan MbtH-Like Protein Interacts with Multiple Nonribosomal Peptide Synthetases in Myxococcus xanthus DK1622
journal, August 2018
- Esquilín-Lebrón, Karla J.; Boynton, Tye O.; Shimkets, Lawrence J.
- Journal of Bacteriology, Vol. 200, Issue 21
TLSMD web server for the generation of multi-group TLS models
journal, January 2006
- Painter, Jay; Merritt, Ethan A.
- Journal of Applied Crystallography, Vol. 39, Issue 1
Structural Basis of the Interaction of MbtH-like Proteins, Putative Regulators of Nonribosomal Peptide Biosynthesis, with Adenylating Enzymes
journal, November 2012
- Herbst, Dominik A.; Boll, Björn; Zocher, Georg
- Journal of Biological Chemistry, Vol. 288, Issue 3
β-Lactone formation during product release from a nonribosomal peptide synthetase
journal, May 2017
- Schaffer, Jason E.; Reck, Margaret R.; Prasad, Neha K.
- Nature Chemical Biology, Vol. 13, Issue 7
X-Ray Crystallography and Electron Microscopy of Cross- and Multi-Module Nonribosomal Peptide Synthetase Proteins Reveal a Flexible Architecture
journal, May 2017
- Tarry, Michael J.; Haque, Asfarul S.; Bui, Khanh Huy
- Structure, Vol. 25, Issue 5
electronic Ligand Builder and Optimization Workbench ( eLBOW ): a tool for ligand coordinate and restraint generation
journal, September 2009
- Moriarty, Nigel W.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 10
Structure of obafluorin: an antibacterial .beta.-lactone from Pseudomonas fluorescens
journal, December 1985
- Tymiak, Adrienne A.; Culver, Catherine A.; Malley, Mary F.
- The Journal of Organic Chemistry, Vol. 50, Issue 26
Structure and Function of the RedJ Protein, a Thioesterase from the Prodiginine Biosynthetic Pathway in Streptomyces coelicolor
journal, May 2011
- Whicher, Jonathan R.; Florova, Galina; Sydor, Paulina K.
- Journal of Biological Chemistry, Vol. 286, Issue 25
Obafluorin, a novel .BETA.-lactone produced by Pseudomonas fluorescens. Taxonomy, fermentation and biological properties.
journal, January 1984
- Wells, J. Scott; Trejo, William H.; Principe, Pacifico A.
- The Journal of Antibiotics, Vol. 37, Issue 7
The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases
journal, August 1999
- Stachelhaus, Torsten; Mootz, Henning D.; Marahiel, Mohamed A.
- Chemistry & Biology, Vol. 6, Issue 8
From deep TLS validation to ensembles of atomic models built from elemental motions. II. Analysis of TLS refinement results by explicit interpretation
journal, June 2018
- Afonine, Pavel V.; Adams, Paul D.; Urzhumtsev, Alexandre
- Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 7
An L-threonine transaldolase is required for L-threo-β-hydroxy-α-amino acid assembly during obafluorin biosynthesis
journal, June 2017
- Scott, Thomas A.; Heine, Daniel; Qin, Zhiwei
- Nature Communications, Vol. 8, Issue 1
Non-ribosomal Propeptide Precursor in Nocardicin A Biosynthesis Predicted from Adenylation Domain Specificity Dependent on the MbtH Family Protein NocI
journal, January 2013
- Davidsen, Jeanne M.; Bartley, David M.; Townsend, Craig A.
- Journal of the American Chemical Society, Vol. 135, Issue 5
Synthetic cycle of the initiation module of a formylating nonribosomal peptide synthetase
journal, January 2016
- Reimer, Janice M.; Aloise, Martin N.; Harrison, Paul M.
- Nature, Vol. 529, Issue 7585
MbtH-Like Proteins as Integral Components of Bacterial Nonribosomal Peptide Synthetases
journal, October 2010
- Felnagle, Elizabeth A.; Barkei, John J.; Park, Hyunjun
- Biochemistry, Vol. 49, Issue 41
β-Lactones as Privileged Structures for the Active-Site Labeling of Versatile Bacterial Enzyme Classes
journal, June 2008
- Böttcher, Thomas; Sieber, Stephan A.
- Angewandte Chemie International Edition, Vol. 47, Issue 24
Structures of a Nonribosomal Peptide Synthetase Module Bound to MbtH-like Proteins Support a Highly Dynamic Domain Architecture
journal, September 2016
- Miller, Bradley R.; Drake, Eric J.; Shi, Ce
- Journal of Biological Chemistry, Vol. 291, Issue 43
Formation of β-Hydroxy Histidine in the Biosynthesis of Nikkomycin Antibiotics
journal, January 2002
- Chen, Huawei; Hubbard, Brian K.; O'Connor, Sarah E.
- Chemistry & Biology, Vol. 9, Issue 1
Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S
journal, July 1997
- Conti, E.
- The EMBO Journal, Vol. 16, Issue 14
A reinvigorated era of bacterial secondary metabolite discovery
journal, February 2015
- Sidebottom, Ashley M.; Carlson, Erin E.
- Current Opinion in Chemical Biology, Vol. 24
Structural Basis for Phosphopantetheinyl Carrier Domain Interactions in the Terminal Module of Nonribosomal Peptide Synthetases
journal, November 2011
- Liu, Ye; Zheng, Tengfei; Bruner, Steven D.
- Chemistry & Biology, Vol. 18, Issue 11
Profiling of β-Lactam Selectivity for Penicillin-Binding Proteins in Streptococcus pneumoniae D39
journal, April 2015
- Kocaoglu, Ozden; Tsui, Ho-Ching T.; Winkler, Malcolm E.
- Antimicrobial Agents and Chemotherapy, Vol. 59, Issue 6
Works referencing / citing this record:
Structures of a dimodular nonribosomal peptide synthetase reveal conformational flexibility
journal, November 2019
- Reimer, Janice M.; Eivaskhani, Maximilian; Harb, Ingrid
- Science, Vol. 366, Issue 6466