Tandemly duplicated CYP82Ds catalyze 14-hydroxylation in triptolide biosynthesis and precursor production in Saccharomyces cerevisiae

Yifeng Zhang, Jie Gao, Lin Ma, Lichan Tu, Tianyuan Hu, Xiaoyi Wu, Ping Su, Yujun Zhao, Yuan Liu, Dan Li, Jiawei Zhou, Yan Yin, Yuru Tong, Huan Zhao, Yun Lu, Jiadian Wang, Wei Gao () and Luqi Huang ()
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Yifeng Zhang: Chinese Academy of Chinese Medical Sciences
Jie Gao: Chinese Academy of Chinese Medical Sciences
Lin Ma: Capital Medical University
Lichan Tu: Zhejiang University City College
Tianyuan Hu: Hangzhou Normal University
Xiaoyi Wu: Capital Medical University
Ping Su: Chinese Academy of Chinese Medical Sciences
Yujun Zhao: Chinese Academy of Chinese Medical Sciences
Yuan Liu: Capital Medical University
Dan Li: Capital Medical University
Jiawei Zhou: Zhejiang University of Technology
Yan Yin: Capital Medical University
Yuru Tong: Capital Medical University
Huan Zhao: Capital Medical University
Yun Lu: Capital Medical University
Jiadian Wang: Capital Medical University
Wei Gao: Capital Medical University
Luqi Huang: Chinese Academy of Chinese Medical Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Triptolide is a valuable multipotent antitumor diterpenoid in Tripterygium wilfordii, and its C-14 hydroxyl group is often selected for modification to enhance both the bioavailability and antitumor efficacy. However, the mechanism for 14-hydroxylation formation remains unknown. Here, we discover 133 kb of tandem duplicated CYP82Ds encoding 11 genes on chromosome 12 and characterize CYP82D274 and CYP82D263 as 14-hydroxylases that catalyze the metabolic grid in triptolide biosynthesis. The two CYP82Ds catalyze the aromatization of miltiradiene, which has been repeatedly reported to be a spontaneous process. In vivo assays and evaluations of the kinetic parameters of CYP82Ds indicate the most significant affinity to dehydroabietic acid among multiple intermediates. The precursor 14-hydroxy-dehydroabietic acid is successfully produced by engineered Saccharomyces cerevisiae. Our study provides genetic elements for further elucidation of the downstream biosynthetic pathways and heterologous production of triptolide and of the currently intractable biosynthesis of other 14-hydroxyl labdane-type secondary metabolites.

Date: 2023
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DOI: 10.1038/s41467-023-36353-y

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