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 of pulvomycin as an inhibitor of the futalosine pathway

The Journal of Antibiotics volume 74, pages 825–829 (2021)Cite this article

Subjects

Abstract

Menaquinone is an essential cofactor in the electron-transfer pathway for bacteria. Menaquinone is biosynthesized from chorismate using either the well-known canonical pathway established by pioneering studies in model microorganisms or the futalosine pathway, which we discovered in Streptomyces. Because Helicobacter pylori, which causes stomach cancer, uses the futalosine pathway and most beneficial intestinal bacteria including lactobacilli use the canonical pathway, the futalosine pathway will be a great target to develop antibiotics specific for H. pylori. Here, we searched for such compounds from metabolites produced by actinomycetes and identified pulvomycin from culture broth of Streptomyces sp. K18-0194 as a specific inhibitor of the futalosine pathway.

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. Bentley R, Meganathan R. Biosynthesis of vitamin K (menaquinone) in bacteria. Microbiol Rev. 1982;46:241–80.

    Article  CAS  Google Scholar 

  2. Meganathan R. Biosynthesis of menaquinone (vitamin K2) and ubiquinone (coenzyme Q): a perspective on enzymatic mechanisms. Vitam Horm. 2001;61:173–218.

    Article  CAS  Google Scholar 

  3. Seto H, et al. Studies on a new biosynthetic pathway for menaquinone. J Am Chem Soc. 2008;130:5614–5.

    Article  CAS  Google Scholar 

  4. Hiratsuka T, et al. An alternative menaquinone biosynthetic pathway operating in microorganisms. Science. 2008;321:1670–3.

    Article  CAS  Google Scholar 

  5. Hiratsuka T, Itoh N, Seto H, Dairi T. Enzymatic properties of futalosine hydrolase, an enzyme essential to a newly identified menaquinone biosynthetic pathway. Biosci Biotechnol Biochem. 2009;73:1137–41.

    Article  CAS  Google Scholar 

  6. Arakawa C, et al. Diversity of the early step of the futalosine pathway. Antimicrob Agents Chemother. 2011;55:913–6.

    Article  CAS  Google Scholar 

  7. Mahanta N, Fedoseyenko D, Dairi T, Begley TP. Menaquinone biosynthesis: formation of aminofutalosine requires a unique radical SAM enzyme. J Am Chem Soc. 2013;135:15318–21.

    Article  CAS  Google Scholar 

  8. Tanaka R, et al. Branched fatty acids inhibit the biosynthesis of menaquinone in Helicobacter pylori. J Antibiot. 2011;64:151–3.

    Article  CAS  Google Scholar 

  9. Ogasawara Y, Kondo K, Ikeda A, Harada R, Dairi T. Identification of tirandamycins as specific inhibitors of the futalosine pathway. J Antibiot. 2017;70:798–800.

    Article  CAS  Google Scholar 

  10. Shimizu Y, Ogasawara Y, Matsumoto A, Dairi T. Aplasmomycin and boromycin are specific inhibitors of the futalosine pathway. J Antibiot. 2018;71:968–70.

    Article  CAS  Google Scholar 

  11. Takami H, Nakasone K, Takaki Y, Maeno G, Sasaki R, Masui N, Fuji F, Hirama C, Nakamura Y, Ogasawara N, Kuhara S, Horikoshi K. Complete genome sequence of the alkaliphilic bacterium Bacillus halodurans and genomic sequence comparison with Bacillus subtilis. Nucleic Acids Res. 2000;28:4317–31.

    Article  CAS  Google Scholar 

  12. Smith RJ, Williams H, Barna JCJ, McDermott IR, Haegele KD, Piriou F, Wagner J, Higgins W. Structure revision of the antibiotic pulvomycin. J Am Chem Soc. 1985;107:2849–57.

    Article  CAS  Google Scholar 

  13. Zief M, Woodside R, Schmitz H. Pulvomycin. Antibiot Chemother. 1957;7:384–6.

  14. Akita E, Maeda K, Umezawa H. Isolation and characterization of labilomycin, a new antibiotc. J Antibiot Ser A. 1963;16:147–51.

    CAS  Google Scholar 

  15. Schwartz JL, Tishler M, Arison BH, Shafer HM, Ōmura S. Identification of mycolutein and pulvomycin as aureothin and labilomycin respectively. J Antibiot Ser A. 1976;16:147–51.

    Google Scholar 

  16. Wolf H, Assmann D, Fischer E. Pulvomycin, an inhibitor of protein biosynthesis preventing ternary complex formation between elongation factor Tu, GTP, and aminoacyl-tRNA. Proc Natl Acad Sci USA. 1978;75:5324–8.

    Article  CAS  Google Scholar 

  17. Schmid B, Anke T, Wolf H. Action of pulvomycin and kirromycin on eukaryotic cells. FEBS Lett. 1978;96:189–91.

    Article  CAS  Google Scholar 

  18. Pingoud A, Block W, Urbanke C, Wolf H. The antibiotics kirromycin and pulvomycin bind to different sites on the elongation factor Tu from Escherichia coli. Eur J Biochem. 1982;123:261–5.

    Article  CAS  Google Scholar 

  19. Parmeggiani A, Krab IM, Okamura S, Nielsen RC, Nyborg J, Nissen P. Structural basis of the action of pulvomycin and GE2270 A on elongation factor Tu. Biochemistry. 2006;45:6846–57.

    Article  CAS  Google Scholar 

  20. McKenzie NL, Thaker M, Koteva K, Hughes DW, Wright GD, Nodwell JR. Induction of antimicrobial activities in heterologous streptomycetes using alleles of the Streptomyces coelicolor gene absA1. J Antibiot. 2010;63:177–82.

    Article  CAS  Google Scholar 

  21. Yamamoto T, et al. Narrow-spectrum inhibitors targeting an alternative menaquinone biosynthetic pathway of Helicobacter pylori. J Infect Chemother. 2016;22:587–92.

    Article  CAS  Google Scholar 

  22. Wang S, et al. A picomolar transition state analogue inhibitor of MTAN as a specific antibiotic for Helicobacter pylori. Biochemistry. 2012;51:6892–4.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas from MEXT, Japan (JSPS KAKENHI Grant Number JP16H06452 to TD), Grants-in-Aid for Scientific Research from JSPS (JP18H03937 to TD JP18K05449 to YO), and the Toyota Riken Scholar Program to YO. We also thank Dr Eri Fukushi at the GC-MS and NMR Laboratory, Graduate School of Agriculture, Hokkaido University for acquiring NMR spectra. We thank Robbie Lewis, MSc, from Edanz (https://jp.edanz.com/) for editing a draft of this manuscript.

Author information

Authors and Affiliations

  1. Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido, Japan

    Yasushi Ogasawara & Tohru Dairi

  2. Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido, Japan

    Shuhei Umetsu

  3. Ōmura Satoshi Memorial Institute, Kitasato University, Minato-ku, Tokyo, Japan

    Yuki Inahashi & Kenichi Nonaka

Authors
  1. Yasushi Ogasawara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuhei Umetsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuki Inahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenichi Nonaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tohru Dairi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TD and YO conceived and designed the experiments. YO and SU isolated and determined the compounds. YI and KN isolated, maintained and characterized the strain. YO and TD wrote the paper. All authors discussed the results and contributed to the final manuscript.

Corresponding authors

Correspondence to Yasushi Ogasawara or Tohru Dairi.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

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

Ogasawara, Y., Umetsu, S., Inahashi, Y. et al. Identification of pulvomycin as an inhibitor of the futalosine pathway. J Antibiot 74, 825–829 (2021). https://doi.org/10.1038/s41429-021-00465-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-021-00465-8

Search

Advanced search

Quick links