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DOI: https://doi.org/10.1016/j.eng.2024.01.012

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Rational Engineering of Secondary Metabolic Pathways in a Heterologous Host to Enable the Biosynthesis of Hibarimicin Derivatives with Enhanced Anti-Melanomic Activity

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  • a State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
    b School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
    c 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
    d Biotechnology Research Center, Toyama Prefectural University, Imizu 939-0398, Japan

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Abstract

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.

Key words： Hibarimicin; Biosynthesis; Heterologous expression; Biosynthetic gene cluster; Rational engineering; Type-II polyketide

Cite this article

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, . Rational Engineering of Secondary Metabolic Pathways in a Heterologous Host to Enable the Biosynthesis of Hibarimicin Derivatives with Enhanced Anti-Melanomic Activity[J]. Engineering, : 0 -0 . DOI: 10.1016/j.eng.2024.01.012

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