Heterologous characterization of mechercharmycin A biosynthesis reveals alternative insights into post-translational modifications for RiPPs.

Autor:	Pei ZF; State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China., Yang MJ; State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China., Zhang K; State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China., Jian XH; College of Chemical Engineering, Sichuan University of Science and Engineering, Zigong 643000, China., Tang GL; State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China; School of Chemistry and Material Sciences, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou 310024, China. Electronic address: gltang@sioc.ac.cn.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2022 Apr 21; Vol. 29 (4), pp. 650-659.e5. Date of Electronic Publication: 2021 Sep 01.
DOI:	10.1016/j.chembiol.2021.08.005
Abstrakt:	Mechercharmycin A (MCM-A) is a marine natural product belonging to a family of polyazole cyclopeptides with remarkable bioactivities and unique structures. Identification, heterologous expression, and genetic characterizations of the MCM biosynthetic gene cluster in Bacillus subtilis revealed that it is a ribosomally synthesized and post-translationally modified peptide (RiPP) possessing complex with distinctive modifications. Based on this heterologous expression system, two MCM analogs with comparable antitumor activity are generated by engineering the biosynthetic pathway. Combinatorial co-production of a precursor peptide with different modifying enzymes in Escherichia coli identifies a different timing of modifications, showing that a tRNA Glu -dependent highly regioselective dehydration is the first modification step, followed by polyazole formation through heterocyclization and dehydrogenation in an N- to C-terminal direction. Therefore, a rational biosynthetic pathway of MCMs is proposed, which unveils a subfamily of azol(in)e-containing RiPPs and sets the stage for further investigations of the enzymatic mechanism and synthetic biology. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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