Rational Engineering of Secondary Metabolic Pathways in a Heterologous Host to Enable the Biosynthesis of Hibarimicin Derivatives with Enhanced Anti-Melanomic Activity
Xiangyang Liu,
Fei-Peng Zhao,
Tian Tian,
Wei-Chen Wang,
Zaizhou Liu,
Qiang Zhou,
Xian-Feng Hou,
Jing Wang,
Wenli Guo,
Shuangjun Lin,
Yasuhiro Igarashi,
Gong-Li Tang
Affiliations
Xiangyang Liu
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
Fei-Peng Zhao
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
Tian Tian
School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
Wei-Chen Wang
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
Zaizhou Liu
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
Qiang Zhou
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
Xian-Feng Hou
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
Jing Wang
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China; School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
Wenli Guo
State Key Laboratory of Microbial Metabolism & Joint International Research Laboratory on Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
Shuangjun Lin
State Key Laboratory of Microbial Metabolism & Joint International Research Laboratory on Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
Yasuhiro Igarashi
Biotechnology Research Center, Toyama Prefectural University, Imizu 939-0398, Japan; Corresponding authors.
Gong-Li Tang
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China; School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Corresponding authors.
A 61-kb biosynthetic gene cluster (BGC), which is accountable for the biosynthesis of hibarimicin (HBM) B from Microbispora rosea subsp. hibaria TP-A0121, was heterologously expressed in Streptomyces coelicolor M1154, which generated a trace of the target products but accumulated a large amount of shunt products. Based on rational analysis of the relevant secondary metabolism, directed engineering of the biosynthetic pathways resulted in the high production of HBM B, as well as new HBM derivates with improved antitumor activity. These results not only establish a biosynthetic system to effectively synthesize HBMs—a class of the largest and most complex Type-II polyketides, with a unique pseudo-dimeric structure—but also set the stage for further engineering and deep investigation of this complex biosynthetic pathway toward potent anticancer drugs.
