Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide
Abstract The diterpenoid triepoxides triptolide and triptonide from Tripterygium wilfordii (thunder god wine) exhibit unique bioactivities with potential uses in disease treatment and as a non-hormonal male contraceptives. Here, we show that cytochrome P450s (CYPs) from the CYP71BE subfamily catalyz...
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Nature Portfolio
2022-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-022-32667-5 |
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| author | Nikolaj Lervad Hansen Louise Kjaerulff Quinn Kalby Heck Victor Forman Dan Staerk Birger Lindberg Møller Johan Andersen-Ranberg |
| author_facet | Nikolaj Lervad Hansen Louise Kjaerulff Quinn Kalby Heck Victor Forman Dan Staerk Birger Lindberg Møller Johan Andersen-Ranberg |
| author_sort | Nikolaj Lervad Hansen |
| collection | DOAJ |
| description | Abstract The diterpenoid triepoxides triptolide and triptonide from Tripterygium wilfordii (thunder god wine) exhibit unique bioactivities with potential uses in disease treatment and as a non-hormonal male contraceptives. Here, we show that cytochrome P450s (CYPs) from the CYP71BE subfamily catalyze an unprecedented 18(4→3) methyl shift required for biosynthesis of the abeo-abietane core structure present in diterpenoid triepoxides and in several other plant diterpenoids. In combination with two CYPs of the CYP82D subfamily, four CYPs from T. wilfordii are shown to constitute the minimal set of biosynthetic genes that enables triptonide biosynthesis using Nicotiana benthamiana and Saccharomyces cerevisiae as heterologous hosts. In addition, co-expression of a specific T. wilfordii cytochrome b 5 (Twcytb 5-A) increases triptonide output more than 9-fold in S. cerevisiae and affords isolation and structure elucidation by NMR spectroscopic analyses of 18 diterpenoids, providing insights into the biosynthesis of diterpenoid triepoxides. Our findings pave the way for diterpenoid triepoxide production via fermentation. |
| format | Article |
| id | doaj-art-aefc7279e2034fbc9995e5406ec82039 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2022-08-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-aefc7279e2034fbc9995e5406ec820392025-08-20T04:03:07ZengNature PortfolioNature Communications2041-17232022-08-0113111210.1038/s41467-022-32667-5Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonideNikolaj Lervad Hansen0Louise Kjaerulff1Quinn Kalby Heck2Victor Forman3Dan Staerk4Birger Lindberg Møller5Johan Andersen-Ranberg6Plant Biochemistry Laboratory, Department of Plant and Environment Sciences, University of CopenhagenDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of CopenhagenPlant Biochemistry Laboratory, Department of Plant and Environment Sciences, University of CopenhagenPlant Biochemistry Laboratory, Department of Plant and Environment Sciences, University of CopenhagenDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of CopenhagenPlant Biochemistry Laboratory, Department of Plant and Environment Sciences, University of CopenhagenPlant Biochemistry Laboratory, Department of Plant and Environment Sciences, University of CopenhagenAbstract The diterpenoid triepoxides triptolide and triptonide from Tripterygium wilfordii (thunder god wine) exhibit unique bioactivities with potential uses in disease treatment and as a non-hormonal male contraceptives. Here, we show that cytochrome P450s (CYPs) from the CYP71BE subfamily catalyze an unprecedented 18(4→3) methyl shift required for biosynthesis of the abeo-abietane core structure present in diterpenoid triepoxides and in several other plant diterpenoids. In combination with two CYPs of the CYP82D subfamily, four CYPs from T. wilfordii are shown to constitute the minimal set of biosynthetic genes that enables triptonide biosynthesis using Nicotiana benthamiana and Saccharomyces cerevisiae as heterologous hosts. In addition, co-expression of a specific T. wilfordii cytochrome b 5 (Twcytb 5-A) increases triptonide output more than 9-fold in S. cerevisiae and affords isolation and structure elucidation by NMR spectroscopic analyses of 18 diterpenoids, providing insights into the biosynthesis of diterpenoid triepoxides. Our findings pave the way for diterpenoid triepoxide production via fermentation.https://doi.org/10.1038/s41467-022-32667-5 |
| spellingShingle | Nikolaj Lervad Hansen Louise Kjaerulff Quinn Kalby Heck Victor Forman Dan Staerk Birger Lindberg Møller Johan Andersen-Ranberg Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide Nature Communications |
| title | Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide |
| title_full | Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide |
| title_fullStr | Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide |
| title_full_unstemmed | Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide |
| title_short | Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide |
| title_sort | tripterygium wilfordii cytochrome p450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide |
| url | https://doi.org/10.1038/s41467-022-32667-5 |
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