Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A
Abstract Backbone N-methylation and macrocyclization improve the pharmacological properties of peptides by enhancing their proteolytic stability, membrane permeability and target selectivity. Borosins are backbone N-methylated peptide macrocycles derived from a precursor protein which contains a pep...
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| Format: | Article |
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Nature Portfolio
2021-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-83106-2 |
| _version_ | 1818994573168345088 |
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| author | Emmanuel Matabaro Hannelore Kaspar Paul Dahlin Daniel L. V. Bader Claudia E. Murar Florian Staubli Christopher M. Field Jeffrey W. Bode Markus Künzler |
| author_facet | Emmanuel Matabaro Hannelore Kaspar Paul Dahlin Daniel L. V. Bader Claudia E. Murar Florian Staubli Christopher M. Field Jeffrey W. Bode Markus Künzler |
| author_sort | Emmanuel Matabaro |
| collection | DOAJ |
| description | Abstract Backbone N-methylation and macrocyclization improve the pharmacological properties of peptides by enhancing their proteolytic stability, membrane permeability and target selectivity. Borosins are backbone N-methylated peptide macrocycles derived from a precursor protein which contains a peptide α-N-methyltransferase domain autocatalytically modifying the core peptide located at its C-terminus. Founding members of borosins are the omphalotins from the mushroom Omphalotus olearius (omphalotins A-I) with nine out of 12 L-amino acids being backbone N-methylated. The omphalotin biosynthetic gene cluster codes for the precursor protein OphMA, the protease prolyloligopeptidase OphP and other proteins that are likely to be involved in other post-translational modifications of the peptide. Mining of available fungal genome sequences revealed the existence of highly homologous gene clusters in the basidiomycetes Lentinula edodes and Dendrothele bispora. The respective borosins, referred to as lentinulins and dendrothelins are naturally produced by L. edodes and D. bispora as shown by analysis of respective mycelial extracts. We produced all three homologous peptide natural products by coexpression of OphMA hybrid proteins and OphP in the yeast Pichia pastoris. The recombinant peptides differ in their nematotoxic activity against the plant pathogen Meloidogyne incognita. Our findings pave the way for the production of borosin peptide natural products and their potential application as novel biopharmaceuticals and biopesticides. |
| first_indexed | 2024-12-20T21:00:06Z |
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| id | doaj.art-8ea7352d2f614b6baa94eeac5342cde2 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-20T21:00:06Z |
| publishDate | 2021-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-8ea7352d2f614b6baa94eeac5342cde22022-12-21T19:26:44ZengNature PortfolioScientific Reports2045-23222021-02-0111111210.1038/s41598-021-83106-2Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin AEmmanuel Matabaro0Hannelore Kaspar1Paul Dahlin2Daniel L. V. Bader3Claudia E. Murar4Florian Staubli5Christopher M. Field6Jeffrey W. Bode7Markus Künzler8Department of Biology, Institute of Microbiology, ETH ZürichDepartment of Biology, Institute of Microbiology, ETH ZürichAgroscope, Phytopathology and Zoology in Fruit and Vegetable ProductionDepartment of Chemistry and Applied Biosciences, Laboratorium Für Organische Chemie, ETH-ZürichDepartment of Chemistry and Applied Biosciences, Laboratorium Für Organische Chemie, ETH-ZürichDepartment of Biology, Institute of Microbiology, ETH ZürichDepartment of Biology, Institute of Microbiology, ETH ZürichDepartment of Chemistry and Applied Biosciences, Laboratorium Für Organische Chemie, ETH-ZürichDepartment of Biology, Institute of Microbiology, ETH ZürichAbstract Backbone N-methylation and macrocyclization improve the pharmacological properties of peptides by enhancing their proteolytic stability, membrane permeability and target selectivity. Borosins are backbone N-methylated peptide macrocycles derived from a precursor protein which contains a peptide α-N-methyltransferase domain autocatalytically modifying the core peptide located at its C-terminus. Founding members of borosins are the omphalotins from the mushroom Omphalotus olearius (omphalotins A-I) with nine out of 12 L-amino acids being backbone N-methylated. The omphalotin biosynthetic gene cluster codes for the precursor protein OphMA, the protease prolyloligopeptidase OphP and other proteins that are likely to be involved in other post-translational modifications of the peptide. Mining of available fungal genome sequences revealed the existence of highly homologous gene clusters in the basidiomycetes Lentinula edodes and Dendrothele bispora. The respective borosins, referred to as lentinulins and dendrothelins are naturally produced by L. edodes and D. bispora as shown by analysis of respective mycelial extracts. We produced all three homologous peptide natural products by coexpression of OphMA hybrid proteins and OphP in the yeast Pichia pastoris. The recombinant peptides differ in their nematotoxic activity against the plant pathogen Meloidogyne incognita. Our findings pave the way for the production of borosin peptide natural products and their potential application as novel biopharmaceuticals and biopesticides.https://doi.org/10.1038/s41598-021-83106-2 |
| spellingShingle | Emmanuel Matabaro Hannelore Kaspar Paul Dahlin Daniel L. V. Bader Claudia E. Murar Florian Staubli Christopher M. Field Jeffrey W. Bode Markus Künzler Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A Scientific Reports |
| title | Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A |
| title_full | Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A |
| title_fullStr | Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A |
| title_full_unstemmed | Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A |
| title_short | Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A |
| title_sort | identification heterologous production and bioactivity of lentinulin a and dendrothelin a two natural variants of backbone n methylated peptide macrocycle omphalotin a |
| url | https://doi.org/10.1038/s41598-021-83106-2 |
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