Aspergillus niger is a superior expression host for the production of bioactive fungal cyclodepsipeptides

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dc.contributor.authorBoecker, Simon
dc.contributor.authorGrätz, Stefan
dc.contributor.authorKerwat, Dennis
dc.contributor.authorAdam, Lutz
dc.contributor.authorSchirmer, David
dc.contributor.authorRichter, Lennart
dc.contributor.authorSchütze, Tabea
dc.contributor.authorPetras, Daniel
dc.contributor.authorSüßmuth, Roderich D.
dc.contributor.authorMeyer, Vera
dc.date.accessioned2019-02-26T16:47:48Z
dc.date.available2019-02-26T16:47:48Z
dc.date.issued2018-03-02
dc.descriptionThe Correction to this article has been published in Fungal Biology and Biotechnology 2018 5:7. https://fungalbiolbiotech.biomedcentral.com/articles/10.1186/s40694-018-0051-8.en
dc.descriptionEine Korrektur zu diesem Artikel wurde publiziert in Fungal Biology and Biotechnology 2018 5:7. https://fungalbiolbiotech.biomedcentral.com/articles/10.1186/s40694-018-0051-8.de
dc.description.abstractBackground: Fungal cyclodepsipeptides (CDPs) are non-ribosomally synthesized peptides produced by a variety of flamentous fungi and are of interest to the pharmaceutical industry due to their anticancer, antimicrobial and anthelmintic bioactivities. However, both chemical synthesis and isolation of CDPs from their natural producers are limited due to high costs and comparatively low yields. These challenges might be overcome by heterologous expression of the respective CDP-synthesizing genes in a suitable fungal host. The well-established industrial fungus Aspergillus niger was recently genetically reprogrammed to overproduce the cyclodepsipeptide enniatin B in g/L scale, suggesting that it can generally serve as a high production strain for natural products such as CDPs. In this study, we thus aimed to determine whether other CDPs such as beauvericin and bassianolide can be produced with high titres in A. niger, and whether the generated expression strains can be used to synthesize new-to-nature CDP derivatives. Results: The beauvericin and bassianolide synthetases were expressed under control of the tuneable Tet-on promoter, and titres of about 350–600 mg/L for bassianolide and beauvericin were achieved when using optimized feeding conditions, respectively. These are the highest concentrations ever reported for both compounds, whether isolated from natural or heterologous expression systems. We also show that the newly established Tet-on based expression strains can be used to produce new-to-nature beauvericin derivatives by precursor directed biosynthesis, including the compounds 12-hydroxyvalerate-beauvericin and bromo-beauvericin. By feeding deuterated variants of one of the necessary precursors (d-hydroxyisovalerate), we were able to purify deuterated analogues of beauvericin and bassianolide from the respective A. niger expression strains. These deuterated compounds could potentially be used as internal standards in stable isotope dilution analyses to evaluate and quantify fungal spoilage of food and feed products. Conclusion: In this study, we show that the product portfolio of A. niger can be expanded from enniatin to other CDPs such as beauvericin and bassianolide, as well as derivatives thereof. This illustrates the capability of A. niger to produce a range of diferent peptide natural products in titres high enough to become industrially relevant.en
dc.description.sponsorshipDFG, EXC 314, Unifying Concepts in Catalysisen
dc.description.sponsorshipEC/FP7/607332/EU/Quantitative Biology for Fungal Secondary Metabolite Producers/QuantFungen
dc.identifier.eissn2054-3085
dc.identifier.urihttps://depositonce.tu-berlin.de/handle/11303/9162
dc.identifier.urihttp://dx.doi.org/10.14279/depositonce-8248
dc.language.isoenen
dc.relation.issupplementedby10.1186/s40694-018-0051-8
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subject.ddc570 Biowissenschaften; Biologieen
dc.subject.otherAspergillus nigeren
dc.subject.othernatural productsen
dc.subject.othernon-ribosomal peptide synthetaseen
dc.subject.othertet-onen
dc.subject.otherenniatinen
dc.subject.otherbeauvericinen
dc.subject.otherbassianolideen
dc.subject.otherprecursor directed biosynthesisen
dc.subject.otherstable isotope dilution analysisen
dc.titleAspergillus niger is a superior expression host for the production of bioactive fungal cyclodepsipeptidesen
dc.typeArticleen
dc.type.versionpublishedVersionen
dcterms.bibliographicCitation.articlenumber4en
dcterms.bibliographicCitation.doi10.1186/s40694-018-0048-3en
dcterms.bibliographicCitation.journaltitleFungal Biology and Biotechnologyen
dcterms.bibliographicCitation.originalpublishernameBioMed Centralen
dcterms.bibliographicCitation.originalpublisherplaceLondonen
dcterms.bibliographicCitation.volume5en
tub.accessrights.dnbfreeen
tub.affiliationFak. 3 Prozesswissenschaften::Inst. Biotechnologie::FG Angewandte und Molekulare Mikrobiologiede
tub.affiliation.facultyFak. 3 Prozesswissenschaftende
tub.affiliation.groupFG Angewandte und Molekulare Mikrobiologiede
tub.affiliation.instituteInst. Biotechnologiede
tub.publisher.universityorinstitutionTechnische Universität Berlinen

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