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Identification of the non-ribosomal peptide synthetase responsible for biosynthesis of the potential anti-cancer drug sansalvamide in Fusarium solani

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Abstract

Sansalvamide is a cyclic pentadepsipeptide produced by Fusarium solani and has shown promising results as potential anti-cancer drug. The biosynthetic pathway has until now remained unidentified, but here we used an Agrobacterium tumefaciens-mediated transformation (ATMT) approach to generate knockout mutants of two candidate non-ribosomal peptide synthetases (NRPS29 and NRPS30). Comparative studies of secondary metabolites in the two deletion mutants and wild type confirmed the absence of sansalvamide in the NRPS30 deletion mutant, implicating this synthetase in the biosynthetic pathway for sansalvamide. Sansalvamide is structurally related to the cyclic hexadepsipeptide destruxin, which both contain an α-hydroxyisocaproic acid (HICA) unit. A gene cluster responsible for destruxin production has previously been identified in Metarhizium robertsii together with a hypothetical biosynthetic pathway. Using comparative bioinformatic analyses of the catalytic domains in the destruxin and sansalvamide NRPSs, we were able to propose a model for sansalvamide biosynthesis. Orthologues of the gene clusters were also identified in species from several other genera including Acremonium chrysogenum and Trichoderma virens, which suggests that the ability to produce compounds related to destruxin and sansalvamide is widespread.

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Acknowledgments

Agrobacterium tumefaciens AGL-1 was a kind gift from Professor Birgitte K. Ahring and PhD students Lei Yang and Istvan Weyda at Aalborg University. Funding for this project was provided by the Aarhus University Research Foundation (AUFF) NANORIPES Centre for Natural Non-Ribosomal Peptide Synthesis (DEB).

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Authors and Affiliations

  1. Department of Molecular Biology and Genetics, NANORIPES Centre for Natural Non-Ribosomal Peptide Synthesis, Aarhus University, Gustav Wieds Vej 10c, 8000, Aarhus C, Denmark

    Patricia Romans-Fuertes, Teis Esben Sondergaard, Frederik T. Hansen, Henriette Giese, Ditlev Egeskov Brodersen & Jens Laurids Sørensen

  2. Department of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220, Aalborg East, Denmark

    Patricia Romans-Fuertes, Teis Esben Sondergaard, Manuela Ilse Helga Sandmann, Rasmus Dam Wollenberg, Henriette Giese & Jens Laurids Sørensen

  3. Department of Systems Biology, Technical University of Denmark, Søltofts Plads, Bygning 221, 2800, Kgs. Lyngby, Denmark

    Kristian Fog Nielsen

  4. Department of Chemistry and Bioscience, Aalborg University, Niels Bohrs Vej 8, 6700, Esbjerg, Denmark

    Jens Laurids Sørensen

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  1. Patricia Romans-Fuertes
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  2. Teis Esben Sondergaard
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  3. Manuela Ilse Helga Sandmann
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  9. Jens Laurids Sørensen
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Correspondence to Jens Laurids Sørensen.

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Communicated by M. Kupiec.

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Romans-Fuertes, P., Sondergaard, T.E., Sandmann, M.I.H. et al. Identification of the non-ribosomal peptide synthetase responsible for biosynthesis of the potential anti-cancer drug sansalvamide in Fusarium solani . Curr Genet 62, 799–807 (2016). https://doi.org/10.1007/s00294-016-0584-4

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