Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Identification, cloning and heterologous expression of biosynthetic gene cluster for desertomycin

The Journal of Antibiotics volume 73, pages 650–654 (2020)Cite this article

Subjects

Abstract

From our in-house microbial genome database of secondary metabolite producers, we identified a candidate biosynthetic gene cluster for desertomycin from Streptomyces nobilis JCM4274. We report herein the cloning of the 127-kb entire gene cluster for desertomycin biosynthesis using bacterial artificial chromosome vector. The entire biosynthetic gene cluster for desertomycin was introduced in the heterologous host, Streptomyces lividans TK23, with an average yield of more than 130 mg l−1.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Pye CR, Bertin MJ, Lokey RS, Gerwick WH, Linington RG. Retrospective analysis of natural products provides insights for future discovery trends. Proc Natl Acad Sci USA. 2017;114:5601–6.

    Article  CAS  Google Scholar 

  2. Palazzolo AME, Simons CLW, Burke MD. The natural productome. Proc Natl Acad Sci USA. 2017;114:5564–6.

    Article  CAS  Google Scholar 

  3. Kautsar SA, et al. MIBiG 2.0: a repository for biosynthetic gene clusters of known function. Nucleic Acids. Res. 2020;48:D454–8.

    PubMed  Google Scholar 

  4. Ichikawa N, et al. DoBISCUIT: a database of secondary metabolite biosynthetic gene clusters. Nucleic Acids Res. 2013;41:D408–14.

    Article  CAS  Google Scholar 

  5. Uri J, Bognar R, Bekesi I, Varga B. Desertomycin, a new crystalline antibiotic with antibacterial and cytostatic action. Nature. 1958;182:401.

    Article  CAS  Google Scholar 

  6. Zerlin M, Thiericke R. Common principles in macrolactone (marginolactone) biosynthesis. Studies on the desertomycin family. J Org Chem. 1994;59:6986–93.

    Article  CAS  Google Scholar 

  7. Hong H, Samborskyy M, Lindner F, Leadlay PF. An amidinohydrolase provides the missing link in the biosynthesis of amino marginolactone antibiotics. Angew Chem Int Ed. 2016;55:1118–23.

    Article  CAS  Google Scholar 

  8. Zhang LH, et al. Characterization of giant modular PKSs provides insight into genetic mechanism for structural diversification of aminopolyol polyketides. Angew Chem Int Ed 2017;56:1740–5.

    Article  CAS  Google Scholar 

  9. Hashimoto T, et al. Novel macrolactam compound produced by the heterologous expression of a large cryptic biosynthetic gene cluster of Streptomyces rochei IFO12908. J Antibiot. 2020;73:171–4.

    Article  CAS  Google Scholar 

  10. Hashimoto T, et al. Biosynthesis of quinolidomicin, the largest known macrolide of terrestrial origin: identification and heterologous expression of a biosynthetic gene cluster over 200 kb. Org Lett. 2018;20:7996–9.

    Article  CAS  Google Scholar 

  11. Hong H, Fill T, Leadlay PF. A common origin for guanidinobutanoate starter units in antifungal natural products. Angew Chem Int Ed. 2013;52:13096–9.

    Article  CAS  Google Scholar 

  12. Reeves CD, et al. Alteration of the substrate specificity of a modular polyketide synthase acyltransferase domain through site-specific mutations. Biochemistry. 2001;40:15464–70.

    Article  CAS  Google Scholar 

  13. Keatinge-Clay AT. The uncommon enzymology of cis-acyltransferase assembly lines. Chem Rev 2017;117:5334–66.

    Article  CAS  Google Scholar 

  14. Young J, et al. Elucidation of gephyronic acid biosynthetic pathway revealed unexpected SAM-dependent methylations. J Nat Prod. 2013;76:2269–76.

    Article  CAS  Google Scholar 

  15. Zhou Y, et al. Iterative mechanism of macrodiolide formation in the anticancer compound conglobatin. Chem Biol. 2015;22:745–54.

    Article  CAS  Google Scholar 

  16. Wenzel SC, et al. Production of the bengamide class of marine natural products in Myxobacteria: biosynthesis and structure–activity relationships. Angew Chem Int Ed. 2015;54:15560–4.

    Article  CAS  Google Scholar 

  17. Keatinge-Clay AT. A tylosin ketoreductase reveals how chirality is determined in polyketides. Chem Biol. 2007;14:898–908.

    Article  CAS  Google Scholar 

  18. Komatsu M, et al. Engineered Streptomyces avermitilis host for heterologous expression of biosynthetic gene cluster for secondary metabolites. ACS Synth Biol. 2013;2:384–96.

    Article  CAS  Google Scholar 

  19. Kim JH, Komatsu M, Shin-ya K, Omura S, Ikeda H. Distribution and functional analysis of the phosphopantetheinyl transferase superfamily in Actinomycetales microorganisms. Proc Natl Acad Sci USA. 2018;115:6828–33.

    Article  Google Scholar 

  20. Jørgensen H, et al. Biosynthesis of macrolactam BE-14106 involves two distinct PKS systems and amino acid processing enzymes for generation of the aminoacyl starter unit. Chem Biol. 2009;16:1109–21.

    Article  Google Scholar 

  21. Tan CH, Kobayashi Y, Kishi Y. Stereochemical assignment of the C21–C38 portion of the desertomycin/oasomycin class of natural products by using universal NMR databases: Proof. Angew Chem Int Ed. 2000;39:4282–4.

    Article  CAS  Google Scholar 

  22. Xie X, Garg A, Khosla C, Cane DE. Elucidation of the cryptic methyl group epimerase activity of dehydratase domains from modular polyketide synthases using a tandem modules epimerase assay. J Am Chem Soc. 2017;139:9507–10.

    Article  CAS  Google Scholar 

  23. Murata M, Matsuoka S, Matsumori N, Paul GK, Tachibana K. Absolute configuration of amphidinol 3, the first complete structure determination from amphidinol homologues: Application of a new configuration analysis based on carbon−hydrogen spin-coupling constants. J Am Chem Soc. 1999;121:870–1.

    Article  CAS  Google Scholar 

  24. Kobayashi H, Shin-ya K, Furihata K, Hayakawa Y, Seto H. Absolute configuration of a novel glutamate receptor antagonist kaitocephalin. Tetrahedron Lett. 2001;42:4021–3.

    Article  CAS  Google Scholar 

  25. Park HR, Chijiwa S, Furihata K, Hayakawa Y, Shin-ya K. Relative and absolute configuration of versipelostatin, a down-regulator of molecular chaperone GRP78 expression. Org lett. 2007;9:1457–60.

    Article  CAS  Google Scholar 

  26. Umeda Y, et al. Absolute structure of prunustatin A, a novel GRP78 molecular chaperone down-regulator. Org Lett. 2007;9:4239–42.

    Article  CAS  Google Scholar 

  27. Kawahara T, Izumikawa M, Takagi M, Shin-ya K. Relative configuration of JBIR-129, a cytotoxic 34-membered glycosidic polyol macrolide from Streptomyces sp. RK74. Org Lett. 2012;14:4434–7.

    Article  CAS  Google Scholar 

  28. Brana AF, et al. Desertomycin G, a new antibiotic with activity against Mycobacterium tuberculosis and human breast tumor cell lines produced by Streptomyces althioticus MSM3, isolated from the Cantabrian sea intertidal macroalgae Ulva sp. Mar Drugs. 2019;17:114.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Japan Agency for Medical Research and Development (AMED) under Grant Number JP17ae0101002 for K.S.

Author information

Authors and Affiliations

  1. National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan

    Takuya Hashimoto, Hikaru Suenaga & Kazuo Shin-ya

  2. Japan Biological Informatics Consortium, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan

    Ikuko Kozone & Junko Hashimoto

  3. Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Kunigami-gun, Okinawa, 904-0495, Japan

    Manabu Fujie & Noriyuki Satoh

  4. Kitasato Institute for Life Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan

    Haruo Ikeda

  5. The Biotechnology Research Center, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan

    Kazuo Shin-ya

  6. Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan

    Kazuo Shin-ya

Authors
  1. Takuya Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ikuko Kozone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junko Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hikaru Suenaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manabu Fujie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Noriyuki Satoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haruo Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazuo Shin-ya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kazuo Shin-ya.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hashimoto, T., Kozone, I., Hashimoto, J. et al. Identification, cloning and heterologous expression of biosynthetic gene cluster for desertomycin. J Antibiot 73, 650–654 (2020). https://doi.org/10.1038/s41429-020-0319-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-020-0319-0

Search

Advanced search

Quick links