Engineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analog
Abstract Cannabinoids are unique meroterpenoids, with cannabigerolic acid (CBGA) serving as a dedicated precursor. This study introduces a fungal aromatic prenyltransferase AscC into the engineered Escherichia coli to catalyze the transfer of C5-C15 terpenoid linear precursors to olivetolic acid. Fo...
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Nature Portfolio
2025-02-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07509-x |
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| author | Qin Yan Yue-Gui Chen Xiao-Wen Yang An Wang Xiao-Ping He Xue Tang Hong Hu Kai Guo Zong-Hua Xiao Yan Liu Sheng-Hong Li |
| author_facet | Qin Yan Yue-Gui Chen Xiao-Wen Yang An Wang Xiao-Ping He Xue Tang Hong Hu Kai Guo Zong-Hua Xiao Yan Liu Sheng-Hong Li |
| author_sort | Qin Yan |
| collection | DOAJ |
| description | Abstract Cannabinoids are unique meroterpenoids, with cannabigerolic acid (CBGA) serving as a dedicated precursor. This study introduces a fungal aromatic prenyltransferase AscC into the engineered Escherichia coli to catalyze the transfer of C5-C15 terpenoid linear precursors to olivetolic acid. Four CBGA derivatives (compounds 1–4) with diverse C5, C10, or C15 prenyl chains are isolated and identified, with compound 4 being an undescribed product featuring a C15 prenyl chain at the C-5 position. Compound 4 demonstrates the highest anti-neuroinflammatory and antibacterial activities, with IC50 values of 3.06 µM for TNF-α and 4.31 µM for IL-6, alongside EC50 values ranging from 0.87 to 3.16 µM against three Gram-positive bacteria. An efficient construct is established by incorporating an additional copy of AscC, resulting in a yield of 14.85 ± 0.91 mg/L of compound 4. Two mutants, L180Y and L180F, are engineered to selectively produce compound 4. These findings provide a foundation for enriching the chemical diversity of bioactive cannabinoid analogs with various prenyl moieties through combinatorial biosynthesis. |
| format | Article |
| id | doaj-art-757749455db04e99922a317eb160df60 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-757749455db04e99922a317eb160df602025-02-09T12:50:51ZengNature PortfolioCommunications Biology2399-36422025-02-01811910.1038/s42003-025-07509-xEngineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analogQin Yan0Yue-Gui Chen1Xiao-Wen Yang2An Wang3Xiao-Ping He4Xue Tang5Hong Hu6Kai Guo7Zong-Hua Xiao8Yan Liu9Sheng-Hong Li10State Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of SciencesState Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of SciencesInnovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of SciencesInnovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese MedicineInnovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese MedicineInnovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese MedicineInnovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese MedicineInnovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of SciencesState Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of SciencesAbstract Cannabinoids are unique meroterpenoids, with cannabigerolic acid (CBGA) serving as a dedicated precursor. This study introduces a fungal aromatic prenyltransferase AscC into the engineered Escherichia coli to catalyze the transfer of C5-C15 terpenoid linear precursors to olivetolic acid. Four CBGA derivatives (compounds 1–4) with diverse C5, C10, or C15 prenyl chains are isolated and identified, with compound 4 being an undescribed product featuring a C15 prenyl chain at the C-5 position. Compound 4 demonstrates the highest anti-neuroinflammatory and antibacterial activities, with IC50 values of 3.06 µM for TNF-α and 4.31 µM for IL-6, alongside EC50 values ranging from 0.87 to 3.16 µM against three Gram-positive bacteria. An efficient construct is established by incorporating an additional copy of AscC, resulting in a yield of 14.85 ± 0.91 mg/L of compound 4. Two mutants, L180Y and L180F, are engineered to selectively produce compound 4. These findings provide a foundation for enriching the chemical diversity of bioactive cannabinoid analogs with various prenyl moieties through combinatorial biosynthesis.https://doi.org/10.1038/s42003-025-07509-x |
| spellingShingle | Qin Yan Yue-Gui Chen Xiao-Wen Yang An Wang Xiao-Ping He Xue Tang Hong Hu Kai Guo Zong-Hua Xiao Yan Liu Sheng-Hong Li Engineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analog Communications Biology |
| title | Engineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analog |
| title_full | Engineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analog |
| title_fullStr | Engineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analog |
| title_full_unstemmed | Engineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analog |
| title_short | Engineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analog |
| title_sort | engineering a promiscuous prenyltransferase for selective biosynthesis of an undescribed bioactive cannabinoid analog |
| url | https://doi.org/10.1038/s42003-025-07509-x |
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