首页|Establishing Modular Cell-Free Expression System for the Biosynthesis of Bicyclomycin from a Chemically Synthesized Cyclodipeptide

Establishing Modular Cell-Free Expression System for the Biosynthesis of Bicyclomycin from a Chemically Synthesized Cyclodipeptide

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Cell-free expression systems have emerged as a versatile and powerful platform for metabolic engineering,biosynthesis and synthetic biology studies.Nevertheless,successful examples of the synthesis of complex natural products using this system are still limited.Bi-cyclomycin,a structurally unique and complex diketopiperazine alkaloid,is a clinically promising antibiotic that selectively inhibits the transcription termination factor Rho.Here,we established a modular cell-free expression system with cascade catalysis for the bio-synthesis of bicyclomycin from a chemically synthesized cyclodipeptide.The six cell-free expressed biosynthetic enzymes,including five iron-and α-ketoglutarate-dependent dioxygenases and one cytochrome P450 monooxygenase,were active in converting their substrates to the corresponding products.The co-expressed enzymes in the cell-free module were able to complete the related partial pathway.In vitro biosynthesis of bicyclomycin was also achieved by reconstituting the entire biosynthetic pathways(i.e.,six enzymes)using the modular cell-free expression system.This study demonstrates that the modular cell-free expression system can be used as a robust and promising platform for the biosynthesis of complex antibiotics.

Natural productsBicyclomycinBiosynthesisIron-and α-ketoglutarate-dependent dioxygenasesCytochrome P450 monooxy-genaseCell-free protein synthesisEnzyme catalysis

Yi-Pei Liu、Yu-Heng Zhao、Wen-Qi Zhang、Lian Wu、Linjuan Huang、Gong-Li Tang、Jun-Bin He

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Shaanxi Natural Carbohydrate Resource Engineering Research Center,College of Food Science and Technology,Northwest University,Xi'an,Shaanxi 710069,China

State Key Laboratory of Chemical Biology,Shanghai Institute of Organic Chemistry,University of Chinese Academy of Sciences(CAS),CAS,Shanghai 200032,China

School of Chemistry and Materials Science,Hangzhou Institute for Advanced Study,University of CAS,1 Sub-lane Xiangshan,Hangzhou,Zhejiang 310024,China

国家重点研发计划国家自然科学基金

2022YFC230310022207117

2024

10.1002/cjoc.202300496

中国化学(英文版)
中国化学会 上海有机化学研究所

中国化学(英文版)

CSTPCD
影响因子：0.848
ISSN：1001-604X
年,卷(期)：2024.42(4)
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