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Induction of secondary metabolite production by hygromycin B and identification of the 1233A biosynthetic gene cluster with a self-resistance gene

The Journal of Antibiotics volume 73, pages 475–479 (2020)Cite this article

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Abstract

We found that the protein synthesis inhibitor hygromycin B induced the production of secondary metabolites, including lucilactaene, NG-391, fusarubin, 1233A, and 1233B, in the filamentous fungus, Fusarium sp. RK97-94. We identified the biosynthetic gene cluster for 1233A, an HMG-CoA synthase inhibitor. The biosynthetic gene cluster consisted of four genes, one of which was involved in conferring self-resistance to 1233A.

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References

  1. Pittenger RC, Wolfe RN, Hoehn MM, Marks PN, Daily WA, Mc GJ. Hygromycin. I. Preliminary studies on the production and biologic activity of a new antibiotic. Antibiot Chemother. 1953;3:1268–78.

    CAS  Google Scholar 

  2. Gritz L, Davies J. Plasmid-encoded hygromycin B resistance: the sequence of hygromycin B phosphotransferase gene and its expression in Escherichia coli and Saccharomyces cerevisiae. Gene. 1983;25:179–88.

    CAS  PubMed  Google Scholar 

  3. Rao RN, Allen NE, Hobbs JN, Jr., Alborn WE, Jr., Kirst HA, Paschal JW. Genetic and enzymatic basis of hygromycin B resistance in Escherichia coli. Antimicrob Agents Chemother. 1983;24:689–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kakeya H, Kageyama S, Nie L, Onose R, Okada G, Beppu T, et al. Lucilactaene, a new cell cycle inhibitor in p53-transfected cancer cells, produced by a Fusarium sp. J Antibiot. 2001;54:850–4.

    CAS  PubMed  Google Scholar 

  5. Sugawara T, Shinonaga H, Simura R, Yoshikawa K, Yamamoto K. Jpn Kokai Tokkyo Koho 319289. 1996 Dec 3.

  6. Kato S, Motoyama T, Futamura Y, Uramoto M, Nogawa T, Hayashi T, et al. Biosynthetic gene cluster identification and biological activity of lucilactaene from Fusarium sp. RK97-94. Biosci Biotechnol Biochem. 2020. https://doi.org/10.1080/09168451.2020.1725419.

  7. Ruelius HW, Gauhe A. Fusarubin, a naphthoquinone coloring matter from Fusaria. Justus Liebigs Ann Chem. 1950;569:38–59.

    CAS  Google Scholar 

  8. Issaq HJ, Barr EW, Wei T, Meyers C, Aszalos A. Thin-layer chromatographic classification of antibiotics exhibiting antitumor properties. J Chromatogr. 1977;133:291–301.

    CAS  PubMed  Google Scholar 

  9. Khan MIH, Sohrab MH, Rony SR, Tareq FS, Hasan CM, Mazid MA. Cytotoxic and antibacterial naphthoquinones from an endophytic fungus, Cladosporium sp. Toxicol Rep. 2016;3:861–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Adorisio S, Fierabracci A, Muscari I, Liberati AM, Cannarile L, Thuy TT, et al. Fusarubin and anhydrofusarubin isolated from A Cladosporium species inhibit cell growth in human cancer cell lines. Toxins. 2019;11:E503.

    PubMed  Google Scholar 

  11. Aldridge DC, Giles D, Turner WB. Antibiotic 1233A: a fungal β-lactone. J Chem Soc Perkin 1. 1971;23:3888–91.

    CAS  PubMed  Google Scholar 

  12. Greenspan MD, Yudkovitz JB, Lo CY, Chen JS, Alberts AW, Hunt VM, et al. Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699. Proc Natl Acad Sci USA. 1987;84:7488–92.

    CAS  PubMed  Google Scholar 

  13. Omura S, Tomoda H, Kumagai H, Greenspan MD, Yodkovitz JB, Chen JS, et al. Potent inhibitory effect of antibiotic 1233A on cholesterol biosynthesis which specifically blocks 3-hydroxy-3-methylglutaryl coenzyme A synthase. J Antibiot. 1987;40:1356–7.

    CAS  PubMed  Google Scholar 

  14. Tomoda H, Kumagai H, Takahashi Y, Tanaka Y, Iwai Y, Omura S. F-244 (1233A), a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A synthase: taxonomy of producing strain, fermentation, isolation and biological properties. J Antibiot. 1988;41:247–9.

    CAS  PubMed  Google Scholar 

  15. Awakawa T, Kaji T, Wakimoto T, Abe I. A heptaketide naphthaldehyde produced by a polyketide synthase from Nectria haematococca. Bioorg Med Chem Lett. 2012;22:4338–40.

    CAS  PubMed  Google Scholar 

  16. Studt L, Wiemann P, Kleigrewe K, Humpf HU, Tudzynski B. Biosynthesis of fusarubins accounts for pigmentation of Fusarium fujikuroi perithecia. Appl Environ Microbiol. 2012;78:4468–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kumagai H, Tomoda H, Omura S. Biosynthesis of antibiotic 1233A (F-244) and preparation of [14C]1233A. J Antibiot. 1992;45:563–7.

    CAS  PubMed  Google Scholar 

  18. Kennedy J, Auclair K, Kendrew SG, Park C, Vederas JC, Hutchinson CR. Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science. 1999;284:1368–72.

    CAS  PubMed  Google Scholar 

  19. Regueira TB, Kildegaard KR, Hansen BG, Mortensen UH, Hertweck C, Nielsen J. Molecular basis for mycophenolic acid biosynthesis in Penicillium brevicompactum. Appl Environ Microbiol. 2011;77:3035–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Yan Y, Liu Q, Zang X, Yuan S, Bat-Erdene U, Nguyen C, et al. Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action. Nature. 2018;559:415–8.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by JSPS KAKENHI under grant numbers JP17H06412, JP17K07742, JP17K07784, and JP18H03945.

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Authors and Affiliations

  1. Chemical Biology Research Group, RIKEN CSRS, Wako, Saitama, Japan

    Sho Kato, Takayuki Motoyama, Masakazu Uramoto, Toshihiko Nogawa & Hiroyuki Osada

  2. Graduate School of Science and Engineering, Saitama University, Sakura, Saitama, Japan

    Sho Kato & Hiroyuki Osada

  3. Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan

    Takashi Kamakura

Authors
  1. Sho Kato
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  2. Takayuki Motoyama
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  3. Masakazu Uramoto
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  4. Toshihiko Nogawa
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  5. Takashi Kamakura
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  6. Hiroyuki Osada
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Contributions

SK purified compounds. SK, MU, and TN determined chemical structures. SK and TM isolated and analyzed the biosynthetic genes. TM, TK, and HO designed the research. SK and TM wrote the paper.

Corresponding authors

Correspondence to Takayuki Motoyama or Hiroyuki Osada.

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Kato, S., Motoyama, T., Uramoto, M. et al. Induction of secondary metabolite production by hygromycin B and identification of the 1233A biosynthetic gene cluster with a self-resistance gene. J Antibiot 73, 475–479 (2020). https://doi.org/10.1038/s41429-020-0295-4

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