title: A non-canonical NRPS is involved in the synthesis of fungisporin and related hydrophobic cyclic tetrapeptides in Penicillium chrysogenum.
abstract: The filamentous fungus Penicillium chrysogenum harbors an astonishing variety of nonribosomal peptide synthetase genes, which encode proteins known to produce complex bioactive metabolites from simple building blocks. Here we report a novel non-canonical tetra-modular nonribosomal peptide synthetase (NRPS) with microheterogenicity of all involved adenylation domains towards their respective substrates. By deleting the putative gene in combination with comparative metabolite profiling various unique cyclic and derived linear tetrapeptides were identified which were associated with this NRPS, including fungisporin. In combination with substrate predictions for each module, we propose a mechanism for a 'trans-acting' adenylation domain.
authors.affiliation: Molecular Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands; Kluyver Centre for Genomics of Industrial Fermentations, Delft, The Netherlands.
authors.forename: Hazrat
authors.initials: H
authors.lastname: Ali
authors.affiliation: Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Marco I
authors.initials: MI
authors.lastname: Ries
authors.affiliation: DSM Biotechnology Center, Delft, The Netherlands.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Lankhorst
authors.affiliation: DSM Biotechnology Center, Delft, The Netherlands.
authors.forename: Rob A M
authors.initials: RA
authors.lastname: van der Hoeven
authors.affiliation: DSM Biotechnology Center, Delft, The Netherlands.
authors.forename: Olaf L
authors.initials: OL
authors.lastname: Schouten
authors.affiliation: Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Netherlands Metabolomics Centre, Leiden University, Leiden, The Netherlands.
authors.forename: Marek
authors.initials: M
authors.lastname: Noga
authors.affiliation: Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Netherlands Metabolomics Centre, Leiden University, Leiden, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hankemeier
authors.affiliation: DSM Biotechnology Center, Delft, The Netherlands.
authors.forename: Noël N M E
authors.initials: NN
authors.lastname: van Peij
authors.affiliation: DSM Biotechnology Center, Delft, The Netherlands; Synthetic Biology and Cell Engineering, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
authors.forename: Roel A L
authors.initials: RA
authors.lastname: Bovenberg
authors.affiliation: Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Netherlands Metabolomics Centre, Leiden University, Leiden, The Netherlands.
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Vreeken
authors.affiliation: Molecular Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands; Kluyver Centre for Genomics of Industrial Fermentations, Delft, The Netherlands.
authors.forename: Arnold J M
authors.initials: AJ
authors.lastname: Driessen
mesh_terms: D000595:Amino Acid Sequence; D015139:Blotting, Southern; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D057927:Hydrophobic and Hydrophilic Interactions; D013058:Mass Spectrometry; D008954:Models, Biological; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000096:biosynthesis* / Q000737:chemistry; D010408:Penicillium chrysogenum / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D010453:Peptide Synthases / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000096:biosynthesis* / Q000737:chemistry; D064210:Secondary Metabolism
chemical_list: D009842:Oligopeptides; D010456:Peptides, Cyclic; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase