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

doi:10.1016/j.eng.2024.01.012

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Engineering ›› 2024, Vol. 38 ›› Issue (7) : 113-123. DOI: 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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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 coeli-color 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.

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Hibarimicin / Biosynthesis / Heterologous expression / Biosynthetic gene cluster / Rational engineering / Type-II polyketide

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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. Engineering, 2024, 38(7): 113‒123 https://doi.org/10.1016/j.eng.2024.01.012

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