title: Identification of the non-ribosomal peptide synthetase responsible for biosynthesis of the potential anti-cancer drug sansalvamide in Fusarium solani.
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.
authors.affiliation: Department of Molecular Biology and Genetics, NANORIPES Centre for Natural Non-Ribosomal Peptide Synthesis, Aarhus University, Gustav Wieds Vej 10c, 8000, Aarhus C, Denmark.|Department of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220, Aalborg East, Denmark.
authors.forename: Patricia
authors.initials: P
authors.lastname: Romans-Fuertes
authors.affiliation: Department of Molecular Biology and Genetics, NANORIPES Centre for Natural Non-Ribosomal Peptide Synthesis, Aarhus University, Gustav Wieds Vej 10c, 8000, Aarhus C, Denmark.|Department of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220, Aalborg East, Denmark.
authors.forename: Teis Esben
authors.initials: TE
authors.lastname: Sondergaard
authors.affiliation: Department of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220, Aalborg East, Denmark.
authors.forename: Manuela Ilse Helga
authors.initials: MI
authors.lastname: Sandmann
authors.affiliation: Department of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220, Aalborg East, Denmark.
authors.forename: Rasmus Dam
authors.initials: RD
authors.lastname: Wollenberg
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Søltofts Plads, Bygning 221, 2800, Kgs. Lyngby, Denmark.
authors.forename: Kristian Fog
authors.initials: KF
authors.lastname: Nielsen
authors.affiliation: Department of Molecular Biology and Genetics, NANORIPES Centre for Natural Non-Ribosomal Peptide Synthesis, Aarhus University, Gustav Wieds Vej 10c, 8000, Aarhus C, Denmark.
authors.forename: Frederik T
authors.initials: FT
authors.lastname: Hansen
authors.affiliation: Department of Molecular Biology and Genetics, NANORIPES Centre for Natural Non-Ribosomal Peptide Synthesis, Aarhus University, Gustav Wieds Vej 10c, 8000, Aarhus C, Denmark.|Department of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220, Aalborg East, Denmark.
authors.forename: Henriette
authors.initials: H
authors.lastname: Giese
authors.affiliation: Department of Molecular Biology and Genetics, NANORIPES Centre for Natural Non-Ribosomal Peptide Synthesis, Aarhus University, Gustav Wieds Vej 10c, 8000, Aarhus C, Denmark.
authors.forename: Ditlev Egeskov
authors.initials: DE
authors.lastname: Brodersen
authors.affiliation: Department of Molecular Biology and Genetics, NANORIPES Centre for Natural Non-Ribosomal Peptide Synthesis, Aarhus University, Gustav Wieds Vej 10c, 8000, Aarhus C, Denmark. jls@bio.aau.dk.|Department of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220, Aalborg East, Denmark. jls@bio.aau.dk.|Department of Chemistry and Bioscience, Aalborg University, Niels Bohrs Vej 8, 6700, Esbjerg, Denmark. jls@bio.aau.dk.
authors.forename: Jens Laurids
authors.identifier: http://orcid.org/0000-0002-2392-5343
authors.initials: JL
authors.lastname: Sørensen
mesh_terms: D000970:Antineoplastic Agents; D047630:Depsipeptides / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology*; D005670:Fusarium / Q000235:genetics* / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D016681:Genome, Fungal; D055442:Metabolome; D055432:Metabolomics; D008954:Models, Biological; D005810:Multigene Family; D010453:Peptide Synthases / Q000235:genetics* / Q000378:metabolism*; D010802:Phylogeny; D064210:Secondary Metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C119376:sansalvamide A; D010453:Peptide Synthases
keywords: Agrobacterium tumefaciens-mediated transformation; Destruxin; Metarhizium robertsii; NRPS; Nectria haematococca; Secondary metabolites