Completing the Biosynthesis of the Clinically Important Diterpenoid Andrographolide in <i>Andrographis Paniculata</i>
Abstract
Abstract Andrographolide is a prominent labdane diterpenoid extracted from Andrographis paniculata with exceptional anti‐inflammatory properties. Commercial production of andrographolide relies exclusively on extraction from plant resources. Although the scaffold of andrographolide ent ‐copalol has previously been biosynthesized, further oxidative modifications remain elusive. In this study, by taking an integrated analysis of transcriptomes and metabolomes, we were able to identify four cytochrome P450 enzymes constituting the minimal set of andrographolide biosynthetic genes. Specifically, ApCYP71D587 catalyzes the conversion of ent ‐copalol to 19‐hydroxy‐ ent ‐copalol. Subsequently, ApCYP71BE50 mediates the formation of the lactone ring, ultimately yielding andrograpanin. Then ApCYP706U5 accomplishes the third step by mediating the C‐3 hydroxylation reaction, thereby allowing the formation of 14‐deoxyandrographolide. Ultimately, ApCYP72F1 completes the biosynthetic generation of andrographolide with C‐14 hydroxylation of the lactone and rearrangement of the olefin bond. In addition, co‐expression of the minimal gene set in N. benthamiana engineered to produce ent ‐copalol feasibly produces andrographolide, thus establishing an innovative metabolic engineering strategy to produce this medicine of historical importance, circumventing the need for plant extraction.
Article Details
Authors (13)
Sifan Wang
Miaomiao Liang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Natural Products, CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs
Weiqiang Chen
Department of Civil and Environmental Engineering and Rice Advanced Materials Institute, Ken Kennedy Institute, Rice University, 6100 Main Street
Huihua Wan
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao‐di Herbs Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences Beijing 100700 China
Xiangxiao Meng
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao‐di Herbs Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences Beijing 100700 China
Xuewen Zhu
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao‐di Herbs Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences Beijing 100700 China
Yuhong Lu
State Key Laboratory of Bioactive Substance and Function of Natural Medicines NHC Key Laboratory of Biosynthesis of Natural Products CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China
Qi Shen
Department of Cancer Institute, Xuzhou Medical University
Chunhong Jiang
State Key Laboratory of Innovative Natural Medicine and TCM Injections Jiangxi Qingfeng Pharmaceutical Co. Ltd. Ganzhou 341008 China
Ning Xie
Shilin Chen
Center for AIE Research, College of Materials Science and Engineering
Meirong Jia
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Natural Products, CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs
Wei Sun