Characterization of the depsidone gene cluster reveals etherification,decarboxylation and multiple halogenations as tailoring steps in depsidone assembly

作     者：Jiafan Yang Zhenbin Zhou Yingying Chen Yongxiang Song Jianhua Ju Jiafan Yang;Zhenbin Zhou;Yingying Chen;Yongxiang Song;Jianhua Ju

作者机构：CAS Key Laboratory of Tropical Marine Bio-resources and EcologyRNAM Center for Marine MicrobiologyGuangdong Key Laboratory of Marine Materia MedicaSouth China Sea Institute of OceanologyChinese Academy of SciencesGuangzhou 510301China University of Chinese Academy of SciencesBeijing 110039China 

出 版 物：《药学学报:英文版》 (Acta Pharmaceutica Sinica B)

年 卷 期：2023年第13卷第9期

页      面：3919-3929页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：funded by the National Natural Science Foundation of China(22037006,U2106207,22077128) Local Innovation and Entrepreneurship Team Project of Guangdong(2019BT02Y262,China) Key Science and Technology Project of Hainan Province(ZDKJ202018,China) Major Project of Basic and Applied Basic Research of Guangdong Province(2019B030302004,China) Key-Area Research and Development Program of Guangdong Province(2020B1111030005,China) Guangdong Provincial Marine Economic Development(Six Major Marine Undertakings,China)Special Fund Project(GDNRC54,China) Open Program of Shenzhen Bay Laboratory(SZBL2021080601006,China) 

主　　题：Depside and depsidone Polyketide synthase Tailoring enzymes Multiple-halogenated Antibacterial activity 

摘      要：Depsides and depsidones have attracted attention for biosynthetic studies due to their broad biological activities and structural *** structure-activity relationships indicated that triple halogenated depsidones display the best anti-pathogenic ***,the gene cluster and the tailoring steps responsible for halogenated depsidone nornidulin(3)remain *** this study,we disclosed the complete biosynthetic pathway of the halogenated depsidone through in vivo gene disruption,heterologous expression and in vitro biochemical *** demonstrated an unusual depside skeleton biosynthesis process mediated by both highly-reducing polyketide synthase and nonreducing polyketide synthase,which is distinct from the common depside skeleton *** skeleton was subsequently modified by two in-cluster enzymes DepG and DepF for the ether bond formation and decarboxylation,*** addition,the decarboxylase DepF exhibited substrate promiscuity for different scaffold ***,and interestingly,we discovered a halogenase encoded remotely from the biosynthetic gene cluster,which catalyzes triple-halogenation to produce the active end product nornidulin(3).These discoveries provide new insights for further understanding the biosynthesis of depsidones and their derivatives.