Sequence-based classification of type II polyketide synthase biosynthetic gene clusters for antiSMASH

Abstract

The software antiSMASH examines microbial genome data to identify and analyze biosynthetic gene clusters for a wide range of natural products. So far, type II polyketide synthase (PKS) gene clusters could only be identified, but no detailed predictions for type II PKS gene clusters could be provided. In this study, an antiSMASH module for analyzing type II PKS gene clusters has been developed. The module detects genes/proteins in the type II PKS gene cluster involved with polyketide biosynthesis and is able to make predictions about the aromatic polyketide product. Predictions include the putative starter unit, the number of malonyl elongations during polyketide biosynthesis, the putative class and the molecular weight of the product. Furthermore, putative cyclization patterns are predicted. The accuracy of the predictions generated with the new PKSII antiSMASH module was evaluated using a leave-one-out cross validation. The prediction module is available in antiSMASH version 5 at https://antismash.secondarymetabolites.org.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    Blin K, Medema MH, Kottmann R et al (2017) The antiSMASH database, a comprehensive database of microbial secondary metabolite biosynthetic gene clusters. Nucleic Acids Res 45:D555–D559. https://doi.org/10.1093/nar/gkw960

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Blin K, Medema MH, Kazempour D et al (2013) antiSMASH 2.0—a versatile platform for genome mining of secondary metabolite producers. Nucleic Acids Res 41:W204–W212. https://doi.org/10.1093/nar/gkt449

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Blin K, Pascal Andreu V, de los Santos EC et al (2018) The antiSMASH database version 2: a comprehensive resource on secondary metabolite biosynthetic gene clusters. Nucleic Acids Res. https://doi.org/10.1093/nar/gky1060

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Blin K, Wolf T, Chevrette MG et al (2017) antiSMASH 4.0—improvements in chemistry prediction and gene cluster boundary identification. Nucleic Acids Res 45:W36–W41. https://doi.org/10.1093/nar/gkx319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Camacho C, Coulouris G, Avagyan V et al (2009) BLAST+: architecture and applications. BMC Bioinform 10:421. https://doi.org/10.1186/1471-2105-10-421

    Article  CAS  Google Scholar 

  6. 6.

    Cane DE, Walsh CT (1999) The parallel and convergent universes of polyketide synthases and nonribosomal peptide synthetases. Chem Biol 6:319–325. https://doi.org/10.1016/S1074-5521(00)80001-0

    Article  Google Scholar 

  7. 7.

    Eddy SR (2011) Accelerated profile HMM searches. PLoS Comput Biol 7:e1002195. https://doi.org/10.1371/journal.pcbi.1002195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32:1792–1797. https://doi.org/10.1093/nar/gkh340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Feng Z, Kallifidas D, Brady SF (2011) Functional analysis of environmental DNA-derived type II polyketide synthases reveals structurally diverse secondary metabolites. Proc Natl Acad Sci 108:12629–12634. https://doi.org/10.1073/pnas.1103921108

    Article  PubMed  Google Scholar 

  10. 10.

    Fernandez-Moreno MA, Martinez E, Boto L et al (1992) Nucleotide sequence and deduced functions of a set of cotranscribed genes of Streptomyces coelicolor A3(2) including the polyketide synthase for the antibiotic actinorhodin. J Biol Chem 267:19278–19290

    CAS  PubMed  Google Scholar 

  11. 11.

    Hadjithomas M, Chen IMA, Chu K et al (2017) IMG-ABC: new features for bacterial secondary metabolism analysis and targeted biosynthetic gene cluster discovery in thousands of microbial genomes. Nucleic Acids Res 45:D560–D565. https://doi.org/10.1093/nar/gkw1103

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Hertweck C, Luzhetskyy A, Rebets Y, Bechthold A (2007) Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork. Nat Prod Rep 24:162–190. https://doi.org/10.1039/B507395M

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Hofeditz T, Unsin C, Wiese J et al (2018) Lysoquinone-TH1, a new polyphenolic tridecaketide produced by expressing the lysolipin minimal PKS II in Streptomyces albus. Antibiotics 7:53. https://doi.org/10.3390/antibiotics7030053

    Article  PubMed Central  Google Scholar 

  14. 14.

    Ichikawa N, Sasagawa M, Yamamoto M et al (2013) DoBISCUIT: a database of secondary metabolite biosynthetic gene clusters. Nucleic Acids Res 41:408–414. https://doi.org/10.1093/nar/gks1177

    Article  CAS  Google Scholar 

  15. 15.

    Katz L, Baltz RH (2016) Natural product discovery: past, present, and future. J Ind Microbiol Biotechnol 43:155–176. https://doi.org/10.1007/s10295-015-1723-5

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Kawasaki T, Moriyama A, Nakagawa K, Imamura N (2016) Cloning and identification of saprolmycin biosynthetic gene cluster from Streptomyces sp. TK08046. Biosci Biotechnol Biochem 80:2144–2150. https://doi.org/10.1080/09168451.2016.1196574

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Kim J, Yi G-SS (2012) PKMiner: a database for exploring type II polyketide synthases. BMC Microbiol 12:169. https://doi.org/10.1186/1471-2180-12-169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Lopez P, Hornung A, Welzel K et al (2010) Isolation of the lysolipin gene cluster of Streptomyces tendae Tu 4042. Gene 461:5–14. https://doi.org/10.1016/j.gene.2010.03.016

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Lukežič T, Lešnik U, Podgoršek A et al (2013) Identification of the chelocardin biosynthetic gene cluster from Amycolatopsis sulphurea: a platform for producing novel tetracycline antibiotics. Microbiol (United Kingdom) 159:2524–2532. https://doi.org/10.1099/mic.0.070995-0

    CAS  Article  Google Scholar 

  20. 20.

    Medema MH, Blin K, Cimermancic P et al (2011) antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res. https://doi.org/10.1093/nar/gkr466

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Medema MH, Kottmann R, Yilmaz P et al (2015) Minimum information about a biosynthetic gene cluster. Nat Chem Biol 11:625–631. https://doi.org/10.1038/nchembio.1890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Medema MH, Fischbach MA (2015) Computational approaches to natural product discovery. Nat Chem Biol 11:639–648. https://doi.org/10.1038/nchembio.1884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Newman DJ, Cragg GM (2016) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79:629–661

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Otten SL, Stutzman-Engwall KJ, Hutchinson CR (1990) Cloning and expression of daunorubicin biosynthesis genes from Streptomyces peucetius and S. peucetius subsp. caesius. J Bacteriol 172:3427–3434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Pickens LB, Tang Y (2009) Decoding and engineering tetracycline biosynthesis. Metab Eng 11:69–75

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Pickens LB, Tang Y (2010) Oxytetracycline biosynthesis. J Biol Chem 285:27509–27515. https://doi.org/10.1074/jbc.R110.130419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Price MN, Dehal PS, Arkin AP (2010) FastTree 2—approximately maximum-likelihood trees for large alignments. PLoS One 5:e9490. https://doi.org/10.1371/journal.pone.0009490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Sandmann A, Dickschat J, Jenke-Kodama H et al (2007) A type II polyketide synthase from the gram-negative bacterium Stigmatella aurantiaca is involved in aurachin alkaloid biosynthesis. Angew Chemie (Int Ed) 46:2712–2716. https://doi.org/10.1002/anie.200603513

    Article  CAS  Google Scholar 

  29. 29.

    Skinnider MA, Dejong CA, Rees PN et al (2015) Genomes to natural products prediction informatics for secondary metabolomes (PRISM). Nucleic Acids Res 43:9645–9662. https://doi.org/10.1093/nar/gkv1012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Skinnider MA, Merwin NJ, Johnston CW, Magarvey NA (2017) PRISM 3: expanded prediction of natural product chemical structures from microbial genomes. Nucleic Acids Res 45:W49–W54. https://doi.org/10.1093/nar/gkx320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Tang Y, Tsai SC, Khosla C (2003) Polyketide chain length control by chain length factor. J Am Chem Soc 125:12708–12709

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Weber T, Blin K, Duddela S et al (2015) antiSMASH 3.0-a comprehensive resource for the genome mining of biosynthetic gene clusters. Nucleic Acids Res 43:W237–W243. https://doi.org/10.1093/nar/gkv437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Zhang M, Hou X-F, Qi L-H et al (2015) Biosynthesis of trioxacarcin revealing a different starter unit and complex tailoring steps for type II polyketide synthase. Chem Sci 6:3440–3447. https://doi.org/10.1039/C5SC00116A

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Zhang Z, Pan H-X, Tang G-L (2017) New insights into bacterial type II polyketide biosynthesis. F1000Research 6:172. https://doi.org/10.12688/f1000research.10466.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Zhou H, Li Y, Tang Y (2010) Cyclization of aromatic polyketides from bacteria and fungi. Nat Prod Rep 27:839–868. https://doi.org/10.1039/b911518h

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Zhu T, Cheng X, Liu Y et al (2013) Deciphering and engineering of the final step halogenase for improved chlortetracycline biosynthesis in industrial Streptomyces aureofaciens. Metab Eng 19:69–78. https://doi.org/10.1016/j.ymben.2013.06.003

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Ziemert N, Alanjary M, Weber T (2016) The evolution of genome mining in microbes—a review. Nat Prod Rep 33:988–1005. https://doi.org/10.1039/C6NP00025H

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by Grants of the Novo Nordisk Foundation [NNF10CC1016517, NNF16OC0021746] to TW.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Kai Blin or Tilmann Weber.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Special Issue “Natural Product Discovery and Development in the Genomic Era 2019".

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 938 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Villebro, R., Shaw, S., Blin, K. et al. Sequence-based classification of type II polyketide synthase biosynthetic gene clusters for antiSMASH. J Ind Microbiol Biotechnol 46, 469–475 (2019). https://doi.org/10.1007/s10295-018-02131-9

Download citation

Keywords

  • Type II polyketide synthases
  • PKS
  • Aromatic polyketides
  • Secondary metabolite
  • Natural product
  • Genome mining