Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol
Abstract Taxol is a widely-applied anticancer drug that inhibits microtubule dynamics in actively replicating cells. Although a minimum 19-step biosynthetic pathway has been proposed and 16 enzymes likely involved have been characterized, stepwise biosynthetic reactions from the well-characterized d...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46583-3 |
| _version_ | 1797259124274102272 |
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| author | Chengshuai Yang Yan Wang Zhen Su Lunyi Xiong Pingping Wang Wen Lei Xing Yan Dawei Ma Guoping Zhao Zhihua Zhou |
| author_facet | Chengshuai Yang Yan Wang Zhen Su Lunyi Xiong Pingping Wang Wen Lei Xing Yan Dawei Ma Guoping Zhao Zhihua Zhou |
| author_sort | Chengshuai Yang |
| collection | DOAJ |
| description | Abstract Taxol is a widely-applied anticancer drug that inhibits microtubule dynamics in actively replicating cells. Although a minimum 19-step biosynthetic pathway has been proposed and 16 enzymes likely involved have been characterized, stepwise biosynthetic reactions from the well-characterized di-oxygenated taxoids to Taxol tetracyclic core skeleton are yet to be elucidated. Here, we uncover the biosynthetic pathways for a few tri-oxygenated taxoids via confirming the critical reaction order of the second and third hydroxylation steps, unearth a taxoid 9α-hydroxylase catalyzing the fourth hydroxylation, and identify CYP725A55 catalyzing the oxetane ester formation via a cascade oxidation-concerted acyl rearrangement mechanism. After identifying a acetyltransferase catalyzing the formation of C7-OAc, the pathway producing the highly-oxygenated 1β-dehydroxybaccatin VI with the Taxol tetracyclic core skeleton is elucidated and its complete biosynthesis from taxa-4(20),11(12)-diene-5α-ol is achieved in an engineered yeast. These systematic studies lay the foundation for the complete elucidation of the biosynthetic pathway of Taxol. |
| first_indexed | 2024-04-24T23:04:26Z |
| format | Article |
| id | doaj.art-10c0872d96c94acab5329aa4471d7d31 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T23:04:26Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-10c0872d96c94acab5329aa4471d7d312024-03-17T12:31:36ZengNature PortfolioNature Communications2041-17232024-03-0115111310.1038/s41467-024-46583-3Biosynthesis of the highly oxygenated tetracyclic core skeleton of TaxolChengshuai Yang0Yan Wang1Zhen Su2Lunyi Xiong3Pingping Wang4Wen Lei5Xing Yan6Dawei Ma7Guoping Zhao8Zhihua Zhou9Key Laboratories of Plant Design and Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of SciencesKey Laboratories of Plant Design and Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of SciencesKey Laboratories of Plant Design and Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of SciencesKey Laboratories of Plant Design and Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of SciencesKey Laboratories of Plant Design and Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of SciencesShanghai Research Institute of Chemical IndustryKey Laboratories of Plant Design and Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of SciencesState Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesKey Laboratories of Plant Design and Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of SciencesKey Laboratories of Plant Design and Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of SciencesAbstract Taxol is a widely-applied anticancer drug that inhibits microtubule dynamics in actively replicating cells. Although a minimum 19-step biosynthetic pathway has been proposed and 16 enzymes likely involved have been characterized, stepwise biosynthetic reactions from the well-characterized di-oxygenated taxoids to Taxol tetracyclic core skeleton are yet to be elucidated. Here, we uncover the biosynthetic pathways for a few tri-oxygenated taxoids via confirming the critical reaction order of the second and third hydroxylation steps, unearth a taxoid 9α-hydroxylase catalyzing the fourth hydroxylation, and identify CYP725A55 catalyzing the oxetane ester formation via a cascade oxidation-concerted acyl rearrangement mechanism. After identifying a acetyltransferase catalyzing the formation of C7-OAc, the pathway producing the highly-oxygenated 1β-dehydroxybaccatin VI with the Taxol tetracyclic core skeleton is elucidated and its complete biosynthesis from taxa-4(20),11(12)-diene-5α-ol is achieved in an engineered yeast. These systematic studies lay the foundation for the complete elucidation of the biosynthetic pathway of Taxol.https://doi.org/10.1038/s41467-024-46583-3 |
| spellingShingle | Chengshuai Yang Yan Wang Zhen Su Lunyi Xiong Pingping Wang Wen Lei Xing Yan Dawei Ma Guoping Zhao Zhihua Zhou Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol Nature Communications |
| title | Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol |
| title_full | Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol |
| title_fullStr | Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol |
| title_full_unstemmed | Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol |
| title_short | Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol |
| title_sort | biosynthesis of the highly oxygenated tetracyclic core skeleton of taxol |
| url | https://doi.org/10.1038/s41467-024-46583-3 |
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