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:

Generation of incednine derivatives by mutasynthesis

The Journal of Antibiotics volume 73, pages 794–797 (2020)Cite this article

Subjects

Abstract

The macrolactam antibiotic incednine, isolated from Streptomyces sp. ML694–90F3, contains a (S)-3-aminobutyric acid moiety in its polyketide aglycon. In this study, we performed mutasynthesis to generate incednine derivatives. We successfully obtained 28-methylincednine by feeding 3-aminopentanoic acid into culture of a strain in which the glutamate 2,3-aminomutase gene idnL4, whose product is responsible for supplying 3-aminobutyric acid, was disrupted. 28-Methylincednine showed similar suppressive activity of the antiapoptotic function of oncoprotein Bcl-xL to that of incednine. Thus, this study highlights the applicability of the mutasynthesis approach in generation of novel β-amino acid-containing macrolactam polyketide derivatives.

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. Futamura Y, Sawa R, Umezawa Y, et al. Discovery of incednine as a potent modulator of the anti-apoptotic function of Bcl-xL from microbial origin. J Am Chem Soc. 2008;130:1822–3.

    Article  CAS  Google Scholar 

  2. Lim YH, Wong FT, Yeo WL, et al. Auroramycin: a potent antibiotic from Streptomyces roseosporus by CRISPR-Cas9 activation. ChemBioChem. 2018;19:1716–9.

    Article  CAS  Google Scholar 

  3. Schulz D, Nachtigall J, Geisen U, et al. Silvalactam, a 24-membered macrolactam antibiotic produced by Streptomyces sp. Tü 6392. J Antibiot. 2012;65:369–72.

    Article  CAS  Google Scholar 

  4. Takaishi M, Kudo F, Eguchi T. Biosynthetic pathway of 24-membered macrolactam glycoside incednine. Tetrahedron. 2008;64:6651–6.

    Article  CAS  Google Scholar 

  5. Takaishi M, Kudo F, Eguchi T. A unique pathway for the 3-aminobutyrate starter unit from L-glutamate through β-glutamate during biosynthesis of the 24-membered macrolactam antibiotic, incednine. Org Lett. 2012;14:4591–3.

    Article  CAS  Google Scholar 

  6. Takaishi M, Kudo F, Eguchi T. Identification of incednine biosynthetic gene cluster: characterization of novel β-glutamate-β-decarboxylase IdnL3. J Antibiot. 2013;66:691–9.

    Article  CAS  Google Scholar 

  7. Cieślak J, Miyanaga A, Takaku R, et al. Biochemical characterization and structural insight into aliphatic β-amino acid adenylation enzymes IdnL1 and CmiS6. Proteins. 2017;85:1238–47.

    Article  Google Scholar 

  8. Cieślak J, Miyanaga A, Takaishi M, et al. Functional and structural characterization of IdnL7, an adenylation enzyme involved in incednine biosynthesis. Acta Crystallogr F Struct Biol Commun. 2019;75:299–306.

    Article  Google Scholar 

  9. Ohtani T, Tsukamoto S, Kanda H, et al. Total synthesis of incednam, the aglycon of incednine. Org Lett. 2010;12:5068–71.

    Article  CAS  Google Scholar 

  10. Miyanaga A, Kudo F, Eguchi T. Mechanisms of β-amino acid incorporation in polyketide macrolactam biosynthesis. Curr Opin Chem Biol. 2016;35:58–64.

    Article  CAS  Google Scholar 

  11. Shindo K, Kamishohara M, Odagawa A, et al. Vicenistatin, a novel 20-membered macrocyclic lactam antitumor antibiotic. J Antibiot. 1993;46:1076–81.

    Article  CAS  Google Scholar 

  12. Ōmura S, Nakagawa A, Shibata K, et al. The structure of hitachimycin, a novel macrocyclic lactam involving β-phenylalanine. Tetrahedron Lett. 1982;23:4713–6.

    Article  Google Scholar 

  13. Ogasawara Y, Katayama K, Minami A, et al. Cloning, sequencing, and functional analysis of the biosynthetic gene cluster of macrolactam antibiotic vicenistatin in Streptomyces halstedii. Chem Biol. 2004;11:79–86.

    CAS  PubMed  Google Scholar 

  14. Kudo F, Kawamura K, Uchino A, et al. Genome mining of the hitachimycin biosynthetic gene cluster: involvement of a phenylalanine-2,3-aminomutase in biosynthesis. ChemBioChem. 2015;16:909–14.

    Article  CAS  Google Scholar 

  15. Miyanaga A. Structure and function of polyketide biosynthetic enzymes: various strategies for production of structurally diverse polyketides. Biosci Biotech Biochem. 2017;81:2227–36.

    Article  CAS  Google Scholar 

  16. Malmierca MG, Pérez-Victoria I, Martín J, et al. New sipanmycin analogues generated by combinatorial biosynthesis and mutasynthesis approaches relying on the substrate flexibility of key enzymes in the biosynthetic pathway. Appl Environ Microbiol. 2019;86:e02453–19.

    Article  Google Scholar 

  17. Malmierca MG, González-Montes L, Pérez-Victoria I, et al. Searching for glycosylated natural products in actinomycetes and identification of novel macrolactams and angucyclines. Front Microbiol. 2018;9:39.

    Article  Google Scholar 

  18. Malmierca MG, Pérez-Victoria I, Martín J, et al. Cooperative involvement of glycosyltransferases in the transfer of amino sugars during the biosynthesis of the macrolactam sipanmycin by Streptomyces sp. strain CS149. Appl Environ Microbiol. 2018;84:e01462–18.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a Grant-in-Aid from the Institute for Fermentation, Osaka (AM), Nagase Science Technology Foundation (FK), Takeda Science Foundation (FK), and by a Grant-in-Aid for Scientific Research on Innovative Areas (23108509 to FK and 16H06451 to TE) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. The authors thank Dr. Yoshio Ando for his kind assistance in operating the Bruker micrOTOF-Q II mass spectrometer. The authors also thank Daisuke Kawasaki and Sotaro Takahashi for obtaining optical rotation data and UV spectra.

Author information

Authors and Affiliations

  1. Department of Chemistry, Tokyo Institute of Technology, 2-12-1 Meguro-ku, O-okayama, Tokyo, 152-8551, Japan

    Akimasa Miyanaga, Ryoma Takaku, Makoto Takaishi, Fumitaka Kudo & Tadashi Eguchi

  2. Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan

    Etsu Tashiro

Authors
  1. Akimasa Miyanaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryoma Takaku
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Makoto Takaishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Etsu Tashiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fumitaka Kudo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tadashi Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tadashi Eguchi.

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

Miyanaga, A., Takaku, R., Takaishi, M. et al. Generation of incednine derivatives by mutasynthesis. J Antibiot 73, 794–797 (2020). https://doi.org/10.1038/s41429-020-0329-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-020-0329-y

Search

Advanced search

Quick links