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| Main Authors: | , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Journal of the American Chemical Society
2024
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/39454086/ |
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| _version_ | 1868266287742844928 |
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| author | Sun, Zhaolun Wu, Mengyue Zhong, Boyuan Wu, Jingshuai Liu, Dong Ren, Jinwei Fan, Shilong Lin, Wenhan Fan, Aili |
| author_facet | Sun, Zhaolun Wu, Mengyue Zhong, Boyuan Wu, Jingshuai Liu, Dong Ren, Jinwei Fan, Shilong Lin, Wenhan Fan, Aili Sun, Zhaolun Wu, Mengyue Zhong, Boyuan Wu, Jingshuai Liu, Dong Ren, Jinwei Fan, Shilong Lin, Wenhan Fan, Aili |
| collection | PubMed - marine biology |
| contents | Target Discovery of Dhilirane-Type Meroterpenoids by Biosynthesis Guidance and Tailoring Enzyme Catalysis. Sun, Zhaolun Wu, Mengyue Zhong, Boyuan Wu, Jingshuai Liu, Dong Ren, Jinwei Fan, Shilong Lin, Wenhan Fan, Aili Terpenes Biocatalysis Cytochrome P-450 Enzyme System Molecular Structure Animals Oxygenases Dhilirane-type meroterpenoids (DMs) featuring a 6/6/6/5/5 ring system represent a rare group of fungal meroterpenoids. To date, merely 11 DMs have been isolated or derived, leaving their chemical diversity predominantly unexplored. Herein, we leverage an understanding of biosynthesis to develop a workflow for discovery of DMs by genome mining, metabolite analysis, and tailoring enzyme catalysis. Twenty-three new DMs, including seven unprecedented scaffolds, were consequently identified. An α-ketoglutarate (α-KG)-dependent oxygenase DhiD was found to catalyze the stereodivergent ring contraction of dhilirolide D to form the dhilirane skeleton; while the cytochrome P450 DhiH reshaped the structural diversity by establishing diverse C-C bonds and oxidation. Crystallographic and mutagenesis experiments provide a molecular basis for the DhiD reaction and its stereodivergent products. Notably, DhiD exhibits substrate-controlled catalytic versatility in the chemical expansion of DMs through ring contraction, hydroxylation, dehydrogenation, epoxidation, isomerization, epimerization, and α-ketol cleavage. Bioassay results demonstrated that the obtained meroterpenoids exhibited anti-inflammatory and insecticidal activities. Our work provides insight into nature's arsenal for DM biosynthesis and the functional versatility of α-KG-dependent oxygenase and P450, which can be applied for target discovery and diversification of DM-type natural products. |
| format | Artículo científico |
| id | pubmed_39454086 |
| institution | PubMed |
| language | en |
| publishDate | 2024 |
| publisher | Journal of the American Chemical Society |
| record_format | pubmed |
| spellingShingle | Target Discovery of Dhilirane-Type Meroterpenoids by Biosynthesis Guidance and Tailoring Enzyme Catalysis. Sun, Zhaolun Wu, Mengyue Zhong, Boyuan Wu, Jingshuai Liu, Dong Ren, Jinwei Fan, Shilong Lin, Wenhan Fan, Aili Terpenes Biocatalysis Cytochrome P-450 Enzyme System Molecular Structure Animals Oxygenases Target Discovery of Dhilirane-Type Meroterpenoids by Biosynthesis Guidance and Tailoring Enzyme Catalysis. Sun, Zhaolun Wu, Mengyue Zhong, Boyuan Wu, Jingshuai Liu, Dong Ren, Jinwei Fan, Shilong Lin, Wenhan Fan, Aili Terpenes Biocatalysis Cytochrome P-450 Enzyme System Molecular Structure Animals Oxygenases Dhilirane-type meroterpenoids (DMs) featuring a 6/6/6/5/5 ring system represent a rare group of fungal meroterpenoids. To date, merely 11 DMs have been isolated or derived, leaving their chemical diversity predominantly unexplored. Herein, we leverage an understanding of biosynthesis to develop a workflow for discovery of DMs by genome mining, metabolite analysis, and tailoring enzyme catalysis. Twenty-three new DMs, including seven unprecedented scaffolds, were consequently identified. An α-ketoglutarate (α-KG)-dependent oxygenase DhiD was found to catalyze the stereodivergent ring contraction of dhilirolide D to form the dhilirane skeleton; while the cytochrome P450 DhiH reshaped the structural diversity by establishing diverse C-C bonds and oxidation. Crystallographic and mutagenesis experiments provide a molecular basis for the DhiD reaction and its stereodivergent products. Notably, DhiD exhibits substrate-controlled catalytic versatility in the chemical expansion of DMs through ring contraction, hydroxylation, dehydrogenation, epoxidation, isomerization, epimerization, and α-ketol cleavage. Bioassay results demonstrated that the obtained meroterpenoids exhibited anti-inflammatory and insecticidal activities. Our work provides insight into nature's arsenal for DM biosynthesis and the functional versatility of α-KG-dependent oxygenase and P450, which can be applied for target discovery and diversification of DM-type natural products. |
| title | Target Discovery of Dhilirane-Type Meroterpenoids by Biosynthesis Guidance and Tailoring Enzyme Catalysis. |
| topic | Terpenes Biocatalysis Cytochrome P-450 Enzyme System Molecular Structure Animals Oxygenases |
| url | https://pubmed.ncbi.nlm.nih.gov/39454086/ |