Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis
Abstract Angucyclines are type II polyketide natural products, often characterized by unusual structural rearrangements through B- or C-ring cleavage of their tetracyclic backbone. While the enzymes involved in B-ring cleavage have been extensively studied, little is known of the enzymes leading to...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-023-01059-1 |
| _version_ | 1797377111566057472 |
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| author | Somayah S. Elsayed Helga U. van der Heul Xiansha Xiao Aleksi Nuutila Laura R. Baars Changsheng Wu Mikko Metsä-Ketelä Gilles P. van Wezel |
| author_facet | Somayah S. Elsayed Helga U. van der Heul Xiansha Xiao Aleksi Nuutila Laura R. Baars Changsheng Wu Mikko Metsä-Ketelä Gilles P. van Wezel |
| author_sort | Somayah S. Elsayed |
| collection | DOAJ |
| description | Abstract Angucyclines are type II polyketide natural products, often characterized by unusual structural rearrangements through B- or C-ring cleavage of their tetracyclic backbone. While the enzymes involved in B-ring cleavage have been extensively studied, little is known of the enzymes leading to C-ring cleavage. Here, we unravel the function of the oxygenases involved in the biosynthesis of lugdunomycin, a highly rearranged C-ring cleaved angucycline derivative. Targeted deletion of the oxygenase genes, in combination with molecular networking and structural elucidation, showed that LugOI is essential for C12 oxidation and maintaining a keto group at C6 that is reduced by LugOII, resulting in a key intermediate towards C-ring cleavage. An epoxide group is then inserted by LugOIII, and stabilized by the novel enzyme LugOV for the subsequent cleavage. Thus, for the first time we describe the oxidative enzymatic steps that form the basis for a wide range of rearranged angucycline natural products. |
| first_indexed | 2024-03-08T19:49:16Z |
| format | Article |
| id | doaj.art-552e4cdb804544a5861a5f3671f524ed |
| institution | Directory Open Access Journal |
| issn | 2399-3669 |
| language | English |
| last_indexed | 2024-03-08T19:49:16Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj.art-552e4cdb804544a5861a5f3671f524ed2023-12-24T12:11:35ZengNature PortfolioCommunications Chemistry2399-36692023-12-016111610.1038/s42004-023-01059-1Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesisSomayah S. Elsayed0Helga U. van der Heul1Xiansha Xiao2Aleksi Nuutila3Laura R. Baars4Changsheng Wu5Mikko Metsä-Ketelä6Gilles P. van Wezel7Department of Molecular Biotechnology, Institute of Biology, Leiden UniversityDepartment of Molecular Biotechnology, Institute of Biology, Leiden UniversityDepartment of Structural Biology, Van Andel InstituteDepartment of Life Technologies, University of TurkuDepartment of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden UniversityState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong UniversityDepartment of Life Technologies, University of TurkuDepartment of Molecular Biotechnology, Institute of Biology, Leiden UniversityAbstract Angucyclines are type II polyketide natural products, often characterized by unusual structural rearrangements through B- or C-ring cleavage of their tetracyclic backbone. While the enzymes involved in B-ring cleavage have been extensively studied, little is known of the enzymes leading to C-ring cleavage. Here, we unravel the function of the oxygenases involved in the biosynthesis of lugdunomycin, a highly rearranged C-ring cleaved angucycline derivative. Targeted deletion of the oxygenase genes, in combination with molecular networking and structural elucidation, showed that LugOI is essential for C12 oxidation and maintaining a keto group at C6 that is reduced by LugOII, resulting in a key intermediate towards C-ring cleavage. An epoxide group is then inserted by LugOIII, and stabilized by the novel enzyme LugOV for the subsequent cleavage. Thus, for the first time we describe the oxidative enzymatic steps that form the basis for a wide range of rearranged angucycline natural products.https://doi.org/10.1038/s42004-023-01059-1 |
| spellingShingle | Somayah S. Elsayed Helga U. van der Heul Xiansha Xiao Aleksi Nuutila Laura R. Baars Changsheng Wu Mikko Metsä-Ketelä Gilles P. van Wezel Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis Communications Chemistry |
| title | Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis |
| title_full | Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis |
| title_fullStr | Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis |
| title_full_unstemmed | Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis |
| title_short | Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis |
| title_sort | unravelling key enzymatic steps in c ring cleavage during angucycline biosynthesis |
| url | https://doi.org/10.1038/s42004-023-01059-1 |
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