Details
| Original language | English |
|---|---|
| Pages (from-to) | 1438-1450 |
| Number of pages | 13 |
| Journal | Chemistry - A European Journal |
| Volume | 27 |
| Issue number | 4 |
| Early online date | 4 Aug 2020 |
| Publication status | Published - 18 Jan 2021 |
Abstract
The diversity of azaphilones in stromatal extracts of the fungus Hypoxylon fragiforme was investigated and linked to their biosynthetic machineries by using bioinformatics. Nineteen azaphilone-type compounds were isolated and characterized by NMR spectroscopy and mass spectrometry, and their absolute stereoconfigurations were assigned by using Mosher ester analysis and electronic circular dichroism spectroscopy. Four unprecedented bis-azaphilones, named hybridorubrins A–D, were elucidated, in addition to new fragirubrins F and G and various known mitorubrin derivatives. Only the hybridorubrins, which are composed of mitorubrin and fragirubrin moieties, exhibited strong inhibition of Staphylococcus aureus biofilm formation. Analysis of the genome of H. fragiforme revealed the presence of two separate biosynthetic gene clusters (BGCs) hfaza1 and hfaza2 responsible for azaphilone formation. While the hfaza1 BGC likely encodes the assembly of the backbone and addition of fatty acid moieties to yield the (R)-configured series of fragirubrins, the hfaza2 BGC contains the necessary genes to synthesise the widely distributed (S)-mitorubrins. This study is the first example of two distant cross-acting fungal BGCs collaborating to produce two families of azaphilones and bis-azaphilones derived therefrom.
Keywords
- biosynthesis, inhibitors, natural products, polyketides, structure elucidation
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- Organic Chemistry
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In: Chemistry - A European Journal, Vol. 27, No. 4, 18.01.2021, p. 1438-1450.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Hybridorubrins A-D
T2 - Azaphilone Heterodimers from Stromata of Hypoxylon fragiforme and Insights into the Biosynthetic Machinery for Azaphilone Diversification
AU - Becker, Kevin
AU - Pfütze, Sebastian
AU - Kuhnert, Eric
AU - Cox, Russell J.
AU - Stadler, Marc
AU - Surup, Frank
N1 - Funding Information: The authors wish to thank Silke Reinecke and Anke Skiba for expert assistance in the lab. We are also grateful for the help of Aileen Gollasch and Klaus‐Peter Conrad for recording the HR‐ESI‐MS spectra, as well as Christel Kakoschke for performing the NMR measurements. Furthermore, Ulrike Beutling is thanked for assistance with MS/MS measurements. We would like to thank Lucile Wendt for providing the stromatal material and the photograph for the table of contents graphic. In addition, we would like to thank Hedda Schrey and Tian Cheng for support with the bioassays as well as Lulu Shao for assistance with the isolation procedure. Boyke Bunk and Cathrin Spröer are acknowledged for PacBio sequencing and Daniel Wibberg for genome annotation. Sebastian Riesinger, Kimberly Borkiet and Natascha Stomberg are thanked for their work in their practical laboratory courses. K.B., E.K., R.J.C., and M.S. are grateful for a grant from the Deutsche Forschungsgemeinschaft (DFG CO 1328/4‐1) in the Priority Programme ′′Taxon‐Omics: New Approaches for Discovering and Naming Biodiversity′′ (SPP 1991). Open access funding enabled and organized by Projekt DEAL.
PY - 2021/1/18
Y1 - 2021/1/18
N2 - The diversity of azaphilones in stromatal extracts of the fungus Hypoxylon fragiforme was investigated and linked to their biosynthetic machineries by using bioinformatics. Nineteen azaphilone-type compounds were isolated and characterized by NMR spectroscopy and mass spectrometry, and their absolute stereoconfigurations were assigned by using Mosher ester analysis and electronic circular dichroism spectroscopy. Four unprecedented bis-azaphilones, named hybridorubrins A–D, were elucidated, in addition to new fragirubrins F and G and various known mitorubrin derivatives. Only the hybridorubrins, which are composed of mitorubrin and fragirubrin moieties, exhibited strong inhibition of Staphylococcus aureus biofilm formation. Analysis of the genome of H. fragiforme revealed the presence of two separate biosynthetic gene clusters (BGCs) hfaza1 and hfaza2 responsible for azaphilone formation. While the hfaza1 BGC likely encodes the assembly of the backbone and addition of fatty acid moieties to yield the (R)-configured series of fragirubrins, the hfaza2 BGC contains the necessary genes to synthesise the widely distributed (S)-mitorubrins. This study is the first example of two distant cross-acting fungal BGCs collaborating to produce two families of azaphilones and bis-azaphilones derived therefrom.
AB - The diversity of azaphilones in stromatal extracts of the fungus Hypoxylon fragiforme was investigated and linked to their biosynthetic machineries by using bioinformatics. Nineteen azaphilone-type compounds were isolated and characterized by NMR spectroscopy and mass spectrometry, and their absolute stereoconfigurations were assigned by using Mosher ester analysis and electronic circular dichroism spectroscopy. Four unprecedented bis-azaphilones, named hybridorubrins A–D, were elucidated, in addition to new fragirubrins F and G and various known mitorubrin derivatives. Only the hybridorubrins, which are composed of mitorubrin and fragirubrin moieties, exhibited strong inhibition of Staphylococcus aureus biofilm formation. Analysis of the genome of H. fragiforme revealed the presence of two separate biosynthetic gene clusters (BGCs) hfaza1 and hfaza2 responsible for azaphilone formation. While the hfaza1 BGC likely encodes the assembly of the backbone and addition of fatty acid moieties to yield the (R)-configured series of fragirubrins, the hfaza2 BGC contains the necessary genes to synthesise the widely distributed (S)-mitorubrins. This study is the first example of two distant cross-acting fungal BGCs collaborating to produce two families of azaphilones and bis-azaphilones derived therefrom.
KW - biosynthesis
KW - inhibitors
KW - natural products
KW - polyketides
KW - structure elucidation
UR - http://www.scopus.com/inward/record.url?scp=85093966698&partnerID=8YFLogxK
U2 - 10.1002/chem.202003215
DO - 10.1002/chem.202003215
M3 - Article
VL - 27
SP - 1438
EP - 1450
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 4
ER -