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 

机构地区：[1]CAS Key Laboratory of Tropical Marine Bio-resources and Ecology,RNAM Center for Marine Microbiology,Guangdong Key Laboratory of Marine Materia Medica,South China Sea Institute of Oceanology,Chinese Academy of Sciences,Guangzhou 510301,China [2]University of Chinese Academy of Sciences,Beijing 110039,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第9期3919-3929,共11页药学学报（英文版）

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(GDNRC[2021]54,China);Open Program of Shenzhen Bay Laboratory(SZBL2021080601006,China)。

摘　　要：Depsides and depsidones have attracted attention for biosynthetic studies due to their broad biological activities and structural diversity.Previous structure-activity relationships indicated that triple halogenated depsidones display the best anti-pathogenic activity.However,the gene cluster and the tailoring steps responsible for halogenated depsidone nornidulin(3)remain enigmatic.In this study,we disclosed the complete biosynthetic pathway of the halogenated depsidone through in vivo gene disruption,heterologous expression and in vitro biochemical experiments.We 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 biosynthesis.This skeleton was subsequently modified by two in-cluster enzymes DepG and DepF for the ether bond formation and decarboxylation,respectively.In addition,the decarboxylase DepF exhibited substrate promiscuity for different scaffold substrates.Finally,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.

关 键 词：Depside and depsidone Polyketide synthase Tailoring enzymes Multiple-halogenated Antibacterial activity 

分 类 号：R915[医药卫生—微生物与生化药学]