Abstract
Modular biosynthetic clusters are responsible for the synthesis of many important pharmaceutical products. They include polyketide synthases (PKS clusters), non-ribosomal synthetases (NRPS clusters), and mixed clusters (containing both PKS and NRPS modules). The ClustScan database (CSDB) contains highly annotated descriptions of 170 clusters. The database has a hierarchical organization, which allows easy extraction of DNA and protein sequences of polypeptides, modules, and domains as well as an organization of the annotation so as to be able to predict the product chemistry to view it or export it in a standard SMILES format. The recombinant ClustScan database contains information about predicted recombinants between PKS clusters. The recombinants are generated by modeling homologous recombination and are associated with annotation and prediction of product chemistry automatically generated by the model. The database contains over 20,000 recombinants and is a resource for in silico approaches to detecting promising new compounds. Methods are available to construct the corresponding recombinants in the laboratory.
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References
Anand S, Prasad MV, Yadav G, Kumar N, Shehara J, Ansari MZ, Mohanty D (2010) SBSPKS: structure-based sequence analysis of polyketide synthases. Nucleic Acids Res 38:W487–W496. doi:10.1093/nar/gkq340
Ansari MZ, Yadav G, Gokhale RS, Mohanty D (2004) NRPS-PKS: a knowledge-based resource for analysis of NRPS/PKS megasynthases. Nucleic Acids Res 32:405–413. doi:10.1093/nar/gkh359
Blažič M, Lisfi M, Starcevic A, Baranasic D, Goranovič D, Fujs Š, Kuščer E, Kosec G, Petković H, Cullum J, Hranueli D, Zucko J (2012) Annotation of modular PKS and NRPS gene clusters in the genomic DNA of Streptomyces tsukubaensis NRRL18488. Appl Environ Microbiol 78:8183–8190. doi:10.1128/AEM.01891-12
Boddy CK, Christopher N (2013) ClusterMine360: a database of microbial PKS/NRPS biosynthesis. Nucleic Acid Res 41(Database issue):D402–D407. doi:10.1093/nar/gks993
Caboche S, Pupin M, Leclère V, Fontaine A, Jacques P, Kucherov G (2008) NORINE: a database of nonribosomal peptides. Nucleic Acids Res 36:D326–D331. doi:10.1093/nar/gkm792
Demain AL, Sanchez S (2009) Microbial drug discovery: 80 years of progress. J Antibiot (Tokyo) 62:5–16. doi:10.1038/ja.2008.16
Donadio S, Monciardini P, Sosio M (2007) Polyketide synthases and nonribosomal peptide synthetases: the emerging view from bacterial genomics. Nat Prod Rep 24:1073–1109. doi:10.1039/B514050C
Hertweck C (2009) The biosynthetic logic of polyketide diversity. Angew Chem Int Ed Engl 48:4688–4716. doi:10.1002/anie.200806121
Hranueli D, Cullum J, Basrak B, Goldstein P, Long PF (2005) Plasticity of the Streptomyces genome—evolution and engineering of new antibiotics. Curr Med Chem 12:1697–1704. doi:10.2174/0929867054367176
Hranueli D, Starcevic A, Zucko J, Rojas JD, Diminic J, Baranasic D, Gacesa R, Padilla G, Long PF, Cullum J (2013) Synthetic biology: a novel approach for the construction of industrial microorganisms. Food Technol Biotechnol 51:3–11
Ichikawa N, Sasagawa M, Yamamoto M, Komaki H, Yoshida Y, Yamazaki S, Fujita N (2013) DoBISCUIT: a database of secondary metabolite biosynthetic gene clusters. Nucleic Acids Res 41(Database issue):D408–D414. doi:10.1093/nar/gks1177
Jenke-Kodama H, Dittmann E (2009) Bioinformatic perspectives on NRPS/PKS megasynthases: advances and challenges. Nat Prod Rep 26:874–883. doi:10.1039/B810283J
Johnston C, Ibrahim A, Magarvey N (2012) Informatic strategies for the discovery of polyketides and nonribosomal peptides. Med Chem Commun 3:932–937. doi:10.1039/c2md20120h
Kalyaanamoorthy S, Chen YP (2011) Structure-based drug design to augment hit discovery. Drug Discov Today 16:831–839. doi:10.1016/j.drudis.2011.07.006
Kopp F, Marahiel MA (2007) Where chemistry meets biology: the chemoenzymatic synthesis of nonribosomal peptides and polyketides. Curr Opin Biotechnol 18:513–520. doi:10.1016/j.copbio.2007.09.009
Li MHT, Ung PMU, Zajkowski J, Garneau-Tsodikova S, Sherman DH (2009) Automated genome mining for natural products. BMC Bioinform 10:185. doi:10.1186/1471-2105-10-185
Medema MH, Blin K, Cimermancic P, de Jager V, Zakrzewski P, Fischbach MA, Weber T, Takano E, Breitling R (2011) antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res 39:W339–W346. doi:10.1093/nar/gkr466
Neumann H, Neumann-Staubitz P (2010) Synthetic biology approaches in drug discovery and pharmaceutical biotechnology. Appl Microbiol Biotechnol 87:75–86. doi:10.1007/s00253-010-2578-3
Rausch C, Weber T, Kohlbacher O, Wohlleben W, Huson DH (2005) Specificity prediction of adenylation domains in nonribosomal peptide synthetases (NRPS) using transductive support vector machines (TSVMs). Nucleic Acids Res 33:5799–5808. doi:10.1093/nar/gki885
Röttig M, Medema MH, Blin K, Weber T, Rausch C, Kohlbacher O (2011) NRPSpredictor2—a web server for predicting NRPS adenylation domain specificity. Nucleic Acids Res 39:W362–W367. doi:10.1093/nar/gkr323
Sattely ES, Fischbach MA, Walsh CT (2008) Total biosynthesis: in vitro reconstitution of polyketide and nonribosomal peptide pathways. Nat Prod Rep 25:757–793. doi:10.1039/b801747f
Starcevic A, Zucko J, Simunkovic J, Long PF, Cullum J, Hranueli D (2008) ClustScan: an integrated program package for the semi-automatic annotation of modular biosynthetic gene clusters and in silico prediction of novel chemical structures. Nucleic Acids Res 36:6882–6892. doi:10.1093/nar/gkn685
Starcevic A, Diminic J, Zucko J, Elbekali M, Schlosser Z, Lisfi M, Vukelic A, Long PF, Hranueli D, Cullum J (2011) A novel docking domain interface model that can predict recombination between homoeologous modular biosynthetic gene clusters. J Ind Microbiol Biotechnol 38:1295–1304. doi:10.1007/s10295-010-0909-0
Starcevic A, Wolf K, Diminic J, Zucko J, Trninic Ruzic I, Long PF, Hranueli D, Cullum J (2012) Recombinatorial biosynthesis of polyketides. J Ind Microbiol Biotechnol 39:503–511. doi:10.1007/s10295-011-1049-x
Tae H, Kong EB, Park K (2007) ASMPKS: an analysis system for modular polyketide synthases. BMC Bioinform 8:327. doi:10.1186/1471-2105-8-327
Weber T, Rausch C, Lopez P, Hoof I, Gaykova V, Huson DH, Wohlleben W (2009) CLUSEAN: a computer-based framework for the automated analysis of bacterial secondary metabolite biosynthetic gene clusters. J Bacterol 140:13–17. doi:10.1016/j.jbiotec.2009.01.007
Weininger D (1988) SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules. J Chem Inf Comput Sci 28:31–36. doi:10.1021/ci00057a005
Wong FT, Khosla C (2012) Combinatorial biosynthesis of polyketides-a perspective. Curr Opin Chem Biol 16:117–123. doi:10.1016/j.cbpa.2012.01.018
Yadav G, Gokhale RS, Mohanty D (2003) SEARCHPKS: a program for detection and analysis of polyketide synthase domains. Nucleic Acids Res 31:3654–3658. doi:10.1093/nar/gkg607
Zazopoulos E, Huang K, Staffa A, Liu W, Bachmann BO, Nonaka K, Ahlert J, Thorson JS, Shen B, Farnet CM (2003) A genomics-guided approach for discovering and expressing cryptic metabolic pathways. Nat Biotechnol 21:187–190. doi:10.1038/nbt784
Zotchev SB, Stepanchikova AV, Sergeyko AP, Sobolev BN, Filimonov DA, Poroikov VV (2006) Rational design of macrolides by virtual screening of combinatorial libraries generated through in silico manipulation of polyketide synthases. J Med Chem 49:2077–2087. doi:10.1021/jm051035i
Zucko J, Starcevic A, Diminic J, Elbekali M, Lisfi M, Long PF, Cullum J, Hranueli D (2010) From DNA sequences to chemical structures—methods for mining microbial genomic and metagenomic datasets for new natural products. Food Technol Biotechnol 48:234–242
Zucko J, Cullum J, Hranueli D, Long PF (2011) Evolutionary dynamics of modular polyketide synthases, with implications for protein design and engineering. J Antibiot 64:89–92. doi:10.1038/ja.2010.141
Zucko J, Long PF, Hranueli D, Cullum J (2012) Horizontal gene transfer drives convergent evolution of modular polyketide synthases. J Ind Microbiol Biotechnol 39:1541–1547. doi:10.1007/s10295-012-1149-2
Acknowledgments
This work was supported by the grant 09/5 (to D.H.) from the Croatian Science Foundation, Republic of Croatia and by a cooperation grant of the German Academic Exchange Service (DAAD) and the Ministry of Science, Education and Sports, Republic of Croatia (to D.H. and J.C.). It was also supported by the Leverhulme Trust; Japanese Bio-Industry Association and The School of Pharmacy, University College London (to P.F.L.).
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Diminic, J., Zucko, J., Ruzic, I.T. et al. Databases of the thiotemplate modular systems (CSDB) and their in silico recombinants (r-CSDB). J Ind Microbiol Biotechnol 40, 653–659 (2013). https://doi.org/10.1007/s10295-013-1252-z
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DOI: https://doi.org/10.1007/s10295-013-1252-z