Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides

Kunyavskaya, Olga; Tagirdzhanov, Azat M.; Caraballo-Rodríguez, Andrés Mauricio; Nothias, Louis-Félix; Dorrestein, Pieter C.; Korobeynikov, Anton; Mohimani, Hosein; Gurevich, Alexey

doi:10.3390/metabo11100693

Title: Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides

Journal Article · Mon Oct 11 00:00:00 EDT 2021 · Metabolites

DOI:https://doi.org/10.3390/metabo11100693· OSTI ID:1825143

;

Microbial natural products are a major source of bioactive compounds for drug discovery. Among these molecules, nonribosomal peptides (NRPs) represent a diverse class of natural products that include antibiotics, immunosuppressants, and anticancer agents. Recent breakthroughs in natural product discovery have revealed the chemical structure of several thousand NRPs. However, biosynthetic gene clusters (BGCs) encoding them are known only for a few hundred compounds. Here, we developed Nerpa, a computational method for the high-throughput discovery of novel BGCs responsible for producing known NRPs. After searching 13,399 representative bacterial genomes from the RefSeq repository against 8368 known NRPs, Nerpa linked 117 BGCs to their products. We further experimentally validated the predicted BGC of ngercheumicin from Photobacterium galatheae via mass spectrometry. Nerpa supports searching new genomes against thousands of known NRP structures, and novel molecular structures against tens of thousands of bacterial genomes. The availability of these tools can enhance our understanding of NRP synthesis and the function of their biosynthetic enzymes.

View Journal Article

Cite

Export

Save

Research Organization:: Carnegie Mellon Univ., Pittsburgh, PA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); Russian Foundation for Basic Research (RFBR); Alfred P. Sloan Foundation; National Institutes of Health (NIH); National Science Foundation (NSF); Gordon and Betty Moore Foundation

Grant/Contract Number:: SC0021340; DP2GM137413; DBI2117640; GBMF7622; P41 GM103484; R01 GM107550; 1DP2GM137413-01

OSTI ID:: 1825143

Alternate ID(s):: OSTI ID: 1981161

Journal Information:: Metabolites, Journal Name: Metabolites Vol. 11 Journal Issue: 10; ISSN 2218-1989

Publisher:: MDPI AGCopyright Statement

Country of Publication:: Switzerland

Language:: English

References (55)

Polyketide and nonribosomal peptide retro-biosynthesis and global gene cluster matching Dejong, Chris A.; Chen, Gregory M.; Li, Haoxin Nature Chemical Biology, Vol. 12, Issue 12 https://doi.org/10.1038/nchembio.2188	journal	October 2016
NRPquest: Coupling Mass Spectrometry and Genome Mining for Nonribosomal Peptide Discovery Mohimani, Hosein; Liu, Wei-Ting; Kersten, Roland D. Journal of Natural Products, Vol. 77, Issue 8 https://doi.org/10.1021/np500370c	journal	August 2014
Minimum Information about a Biosynthetic Gene cluster Medema, Marnix H.; Kottmann, Renzo; Yilmaz, Pelin Nature Chemical Biology, Vol. 11, Issue 9 https://doi.org/10.1038/nchembio.1890	journal	August 2015
Specificity prediction of adenylation domains in nonribosomal peptide synthetases (NRPS) using transductive support vector machines (TSVMs) Rausch, C. Nucleic Acids Research, Vol. 33, Issue 18 https://doi.org/10.1093/nar/gki885	journal	October 2005
More than Anticipated – Production of Antibiotics and Other Secondary Metabolites by Bacillus amyloliquefaciens FZB42 Chen, Xiao-Hua; Koumoutsi, Alexandra; Scholz, Romy Journal of Molecular Microbiology and Biotechnology, Vol. 16, Issue 1-2 https://doi.org/10.1159/000142891	journal	January 2009
Modular Peptide Synthetases Involved in Nonribosomal Peptide Synthesis Marahiel, Mohamed A.; Stachelhaus, Torsten; Mootz, Henning D. Chemical Reviews, Vol. 97, Issue 7 https://doi.org/10.1021/cr960029e	journal	November 1997
Dereplication of microbial metabolites through database search of mass spectra Mohimani, Hosein; Gurevich, Alexey; Shlemov, Alexander Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-06082-8	journal	October 2018
A machine learning-based method for prediction of macrocyclization patterns of polyketides and non-ribosomal peptides Agrawal, Priyesh; Mohanty, Debasisa Bioinformatics, Vol. 37, Issue 5 https://doi.org/10.1093/bioinformatics/btaa851	journal	November 2020
Phylogenetic analysis of condensation domains in NRPS sheds light on their functional evolution Rausch, Christian; Hoof, Ilka; Weber, Tilmann BMC Evolutionary Biology, Vol. 7, Issue 1 https://doi.org/10.1186/1471-2148-7-78	journal	January 2007
SANDPUMA: ensemble predictions of nonribosomal peptide chemistry reveal biosynthetic diversity across Actinobacteria Chevrette, Marc G.; Aicheler, Fabian; Kohlbacher, Oliver Bioinformatics, Vol. 33, Issue 20 https://doi.org/10.1093/bioinformatics/btx400	journal	June 2017
Biosynthetic Pathway for Mannopeptimycins, Lipoglycopeptide Antibiotics Active against Drug-Resistant Gram-Positive Pathogens Magarvey, Nathan A.; Haltli, Brad; He, Min Antimicrobial Agents and Chemotherapy, Vol. 50, Issue 6 https://doi.org/10.1128/AAC.01545-05	journal	June 2006
Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity Kim, Eunji; Shin, Yern-Hyerk; Kim, Tae Ho Biomolecules, Vol. 9, Issue 11 https://doi.org/10.3390/biom9110672	journal	October 2019
Bacterial Biosynthesis and Maturation of the Didemnin Anti-cancer Agents Xu, Ying; Kersten, Roland D.; Nam, Sang-Jip Journal of the American Chemical Society, Vol. 134, Issue 20 https://doi.org/10.1021/ja301735a	journal	April 2012
Structure and Biosynthesis of Amychelin, an Unusual Mixed-Ligand Siderophore from Amycolatopsis sp. AA4 Seyedsayamdost, Mohammad R.; Traxler, Matthew F.; Zheng, Shao-Liang Journal of the American Chemical Society, Vol. 133, Issue 30 https://doi.org/10.1021/ja203577e	journal	July 2011
Comprehensive prediction of secondary metabolite structure and biological activity from microbial genome sequences Skinnider, Michael A.; Johnston, Chad W.; Gunabalasingam, Mathusan Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-19986-1	journal	November 2020
RiPPMiner: a bioinformatics resource for deciphering chemical structures of RiPPs based on prediction of cleavage and cross-links Agrawal, Priyesh; Khater, Shradha; Gupta, Money Nucleic Acids Research, Vol. 45, Issue W1 https://doi.org/10.1093/nar/gkx408	journal	May 2017
An Iterative Nonribosomal Peptide Synthetase Assembles the Pyrrole-Amide Antibiotic Congocidine in Streptomyces ambofaciens Juguet, Maud; Lautru, Sylvie; Francou, François-Xavier Chemistry & Biology, Vol. 16, Issue 4 https://doi.org/10.1016/j.chembiol.2009.03.010	journal	April 2009
Dereplication of peptidic natural products through database search of mass spectra Mohimani, Hosein; Gurevich, Alexey; Mikheenko, Alla Nature Chemical Biology, Vol. 13, Issue 1 https://doi.org/10.1038/nchembio.2219	journal	October 2016
Pep2Path: Automated Mass Spectrometry-Guided Genome Mining of Peptidic Natural Products Medema, Marnix H.; Paalvast, Yared; Nguyen, Don D. PLoS Computational Biology, Vol. 10, Issue 9 https://doi.org/10.1371/journal.pcbi.1003822	journal	September 2014
StreptomeDB 3.0: an updated compendium of streptomycetes natural products Moumbock, Aurélien F. A.; Gao, Mingjie; Qaseem, Ammar Nucleic Acids Research, Vol. 49, Issue D1 https://doi.org/10.1093/nar/gkaa868	journal	October 2020
Cracking the Nonribosomal Code Ackerley, David F. Cell Chemical Biology, Vol. 23, Issue 5 https://doi.org/10.1016/j.chembiol.2016.05.001	journal	May 2016
Learning from Nature's Drug Factories: Nonribosomal Synthesis of Macrocyclic Peptides Sieber, S. A.; Marahiel, M. A. Journal of Bacteriology, Vol. 185, Issue 24 https://doi.org/10.1128/JB.185.24.7036-7043.2003	journal	December 2003
antiSMASH 2.0—a versatile platform for genome mining of secondary metabolite producers Blin, Kai; Medema, Marnix H.; Kazempour, Daniyal Nucleic Acids Research, Vol. 41, Issue W1 https://doi.org/10.1093/nar/gkt449	journal	May 2013
The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases Stachelhaus, Torsten; Mootz, Henning D.; Marahiel, Mohamed A. Chemistry & Biology, Vol. 6, Issue 8 https://doi.org/10.1016/S1074-5521(99)80082-9	journal	August 1999
antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences Medema, Marnix H.; Blin, Kai; Cimermancic, Peter Nucleic Acids Research, Vol. 39, Issue suppl_2 https://doi.org/10.1093/nar/gkr466	journal	June 2011
antiSMASH 4.0—improvements in chemistry prediction and gene cluster boundary identification Blin, Kai; Wolf, Thomas; Chevrette, Marc G. Nucleic Acids Research, Vol. 45, Issue W1 https://doi.org/10.1093/nar/gkx319	journal	April 2017
Identification of Four New agr Quorum Sensing-Interfering Cyclodepsipeptides from a Marine Photobacterium Kjaerulff, Louise; Nielsen, Anita; Mansson, Maria Marine Drugs, Vol. 11, Issue 12 https://doi.org/10.3390/md11125051	journal	December 2013
Interactive metagenomic visualization in a Web browser Ondov, Brian D.; Bergman, Nicholas H.; Phillippy, Adam M. BMC Bioinformatics, Vol. 12, Issue 1 https://doi.org/10.1186/1471-2105-12-385	journal	September 2011
The antiSMASH database version 3: increased taxonomic coverage and new query features for modular enzymes Blin, Kai; Shaw, Simon; Kautsar, Satria A. Nucleic Acids Research, Vol. 49, Issue D1 https://doi.org/10.1093/nar/gkaa978	journal	November 2020
Photobacterium galatheae sp. nov., a bioactive bacterium isolated from a mussel in the Solomon Sea Machado, Henrique; Giubergia, Sonia; Mateiu, Ramona Valentina International Journal of Systematic and Evolutionary Microbiology, Vol. 65, Issue Pt_12 https://doi.org/10.1099/ijsem.0.000603	journal	December 2015
Assembly-Line Enzymology for Polyketide and Nonribosomal Peptide Antibiotics: Logic, Machinery, and Mechanisms Fischbach, Michael A.; Walsh, Christopher T. Chemical Reviews, Vol. 106, Issue 8 https://doi.org/10.1021/cr0503097	journal	August 2006
rBAN: retro-biosynthetic analysis of nonribosomal peptides Ricart, Emma; Leclère, Valérie; Flissi, Areski Journal of Cheminformatics, Vol. 11, Issue 1 https://doi.org/10.1186/s13321-019-0335-x	journal	February 2019
NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins Pruitt, K. D. Nucleic Acids Research, Vol. 33, Issue Database issue https://doi.org/10.1093/nar/gki025	journal	December 2004
MIBiG 2.0: a repository for biosynthetic gene clusters of known function Kautsar, Satria A.; Blin, Kai; Shaw, Simon Nucleic Acids Research https://doi.org/10.1093/nar/gkz882	journal	October 2019
Discovery of Antimicrobial Lipodepsipeptides Produced by a Serratia sp. within Mosquito Microbiomes Ganley, Jack G.; Carr, Gavin; Ioerger, Thomas R. ChemBioChem, Vol. 19, Issue 15 https://doi.org/10.1002/cbic.201800124	journal	June 2018
On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to Their Use in the Isolation of B. influenzae Fleming, A. Clinical Infectious Diseases, Vol. 2, Issue 1 https://doi.org/10.1093/clinids/2.1.129	journal	January 1980
Automated genome mining for natural products Li, Michael HT; Ung, Peter MU; Zajkowski, James BMC Bioinformatics, Vol. 10, Issue 1 https://doi.org/10.1186/1471-2105-10-185	journal	January 2009
Nonribosomal Peptide Synthesis-Principles and Prospects Süssmuth, Roderich D.; Mainz, Andi Angewandte Chemie International Edition, Vol. 56, Issue 14 https://doi.org/10.1002/anie.201609079	journal	March 2017
Nonribosomal Peptides from Marine Microbes and Their Antimicrobial and Anticancer Potential Agrawal, Shivankar; Acharya, Debabrata; Adholeya, Alok Frontiers in Pharmacology, Vol. 8 https://doi.org/10.3389/fphar.2017.00828	journal	November 2017
Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking Wang, Mingxun; Carver, Jeremy J.; Phelan, Vanessa V. Nature Biotechnology, Vol. 34, Issue 8 https://doi.org/10.1038/nbt.3597	journal	August 2016
Increased diversity of peptidic natural products revealed by modification-tolerant database search of mass spectra Gurevich, Alexey; Mikheenko, Alla; Shlemov, Alexander Nature Microbiology, Vol. 3, Issue 3 https://doi.org/10.1038/s41564-017-0094-2	journal	January 2018
Norine, the knowledgebase dedicated to non-ribosomal peptides, is now open to crowdsourcing Flissi, Areski; Dufresne, Yoann; Michalik, Juraj Nucleic Acids Research, Vol. 44, Issue D1 https://doi.org/10.1093/nar/gkv1143	journal	November 2015
A general method applicable to the search for similarities in the amino acid sequence of two proteins Needleman, Saul B.; Wunsch, Christian D. Journal of Molecular Biology, Vol. 48, Issue 3, p. 443-453 https://doi.org/10.1016/0022-2836(70)90057-4	journal	March 1970
Ohmyungsamycins A and B: Cytotoxic and Antimicrobial Cyclic Peptides Produced by Streptomyces sp. from a Volcanic Island Um, Soohyun; Choi, Tae Joon; Kim, Heegyu The Journal of Organic Chemistry, Vol. 78, Issue 24 https://doi.org/10.1021/jo401974g	journal	November 2013
antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline Blin, Kai; Shaw, Simon; Steinke, Katharina Nucleic Acids Research, Vol. 47, Issue W1 https://doi.org/10.1093/nar/gkz310	journal	April 2019
Characterization of the colistin (polymyxin E1 and E2) biosynthetic gene cluster Tambadou, Fatoumata; Caradec, Thibault; Gagez, Anne-Laure Archives of Microbiology, Vol. 197, Issue 4 https://doi.org/10.1007/s00203-015-1084-5	journal	January 2015
Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining Skinnider, Michael A.; Johnston, Chad W.; Edgar, Robyn E. Proceedings of the National Academy of Sciences, Vol. 113, Issue 42 https://doi.org/10.1073/pnas.1609014113	journal	October 2016
SeMPI 2.0—A Web Server for PKS and NRPS Predictions Combined with Metabolite Screening in Natural Product Databases Zierep, Paul F.; Ceci, Adriana T.; Dobrusin, Ilia Metabolites, Vol. 11, Issue 1 https://doi.org/10.3390/metabo11010013	journal	December 2020
PubChem Substance and Compound databases Kim, Sunghwan; Thiessen, Paul A.; Bolton, Evan E. Nucleic Acids Research, Vol. 44, Issue D1 https://doi.org/10.1093/nar/gkv951	journal	September 2015
NRPSpredictor2—a web server for predicting NRPS adenylation domain specificity Röttig, Marc; Medema, Marnix H.; Blin, Kai Nucleic Acids Research, Vol. 39, Issue suppl_2 https://doi.org/10.1093/nar/gkr323	journal	May 2011
antiSMASH 3.0—a comprehensive resource for the genome mining of biosynthetic gene clusters Weber, Tilmann; Blin, Kai; Duddela, Srikanth Nucleic Acids Research, Vol. 43, Issue W1 https://doi.org/10.1093/nar/gkv437	journal	May 2015
The Natural Products Atlas: An Open Access Knowledge Base for Microbial Natural Products Discovery van Santen, Jeffrey A.; Jacob, Grégoire; Singh, Amrit Leen ACS Central Science, Vol. 5, Issue 11 https://doi.org/10.1021/acscentsci.9b00806	journal	September 2019
Biosynthesis of the cyclooligomer depsipeptide bassianolide, an insecticidal virulence factor of Beauveria bassiana Xu, Yuquan; Orozco, Rousel; Kithsiri Wijeratne, E. M. Fungal Genetics and Biology, Vol. 46, Issue 5 https://doi.org/10.1016/j.fgb.2009.03.001	journal	May 2009
Selective interaction between nonribosomal peptide synthetases is facilitated by short communication-mediating domains Hahn, M.; Stachelhaus, T. Proceedings of the National Academy of Sciences, Vol. 101, Issue 44 https://doi.org/10.1073/pnas.0404932101	journal	October 2004
Seven More Microcystins from Homer Lake Cells: Application of the General Method for Structure Assignment of Peptides Containing .alpha.,.beta.-Dehydroamino Acid Unit(s) Namikoshi, Michio; Sun, Furong; Choi, Byoung Wook The Journal of Organic Chemistry, Vol. 60, Issue 12 https://doi.org/10.1021/jo00117a017	journal	June 1995

Similar Records

AdenPredictor: accurate prediction of the adenylation domain specificity of nonribosomal peptide biosynthetic gene clusters in microbial genomes

Journal Article · Fri Jun 30 00:00:00 EDT 2023 · Bioinformatics · OSTI ID:1825143

Mongia, Mihir; Baral, Romel; Adduri, Abhinav; +6 more

Integrating genomics and metabolomics for scalable non-ribosomal peptide discovery

Journal Article · Fri May 28 00:00:00 EDT 2021 · Nature Communications · OSTI ID:1825143

Behsaz, Bahar; Bode, Edna; Gurevich, Alexey; +13 more

Bioinformatic and Mechanistic Analysis of the Palmerolide PKS-NRPS Biosynthetic Pathway From the Microbiome of an Antarctic Ascidian

Journal Article · Fri Dec 24 00:00:00 EST 2021 · Frontiers in Chemistry · OSTI ID:1825143

Avalon, Nicole E.; Murray, Alison E.; Daligault, Hajnalka Erzsebet; +5 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
natural products
nonribosomal peptides
genome mining
biosynthetic gene clusters
bioinformatics
mass spectrometry
software
machine learning

Title: Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides

Citation Formats

References (55)

Similar Records

Related Subjects