Refactoring and Heterologous Expression of Class III Lanthipeptide Biosynthetic Gene Clusters Lead to the Discovery of N,N-Dimethylated Lantibiotics from Firmicutes.
Refactoring and Heterologous Expression of Class III Lanthipeptide Biosynthetic Gene Clusters Lead to the Discovery of N,N-Dimethylated Lantibiotics from Firmicutes.
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DOI：
10.1021/acschembio.2c00849
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发表时间：
2023-03-17
影响因子：
4
通讯作者：
Li, Jie
中科院分区：
文献类型：
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作者：
Xue, Dan;Shang, Zhuo;Older, Ethan A.;Zhong, Zheng;Pulliam, Conor;Peter, Kyle;Nagarkatti, Mitzi;Nagarkatti, Prakash;Li, Yong-Xin;Li, Jie
Class III lanthipeptides are an emerging subclass of lanthipeptides, representing an underexplored trove of new natural products with potentially broad chemical diversity and important biological activity. Bioinformatic analysis of class III lanthipeptide biosynthetic gene clusters (BGCs) distribution has revealed their high abundance in the phylum Firmicutes. Many of these clusters also feature methyltransferase genes, which likely encode uncommon class III lanthipeptides. However, two hurdles, silent BGCs and low-yielding pathways, have hindered the discovery of class III lanthipeptides from Firmicutes. Here, we report the design and construction of a biosynthetic pathway refactoring and heterologous overexpression strategy which seeks to overcome these hurdles, simultaneously activating and increasing the production of these Firmicutes class III lanthipeptides. Applying our strategy to methyltransferase-containing BGCs, we report the discovery of new class III lanthipeptides from Firmicutes bearing rare N,N-dimethylations. We reveal the importance of the first two amino acids in the N-terminus of the core peptide in controlling the methyltransferase dimethylation activity. Leveraging this feature, we engineer class III lanthipeptides to enable N,N-dimethylation, resulting in significantly increased antibacterial activity. Furthermore, the refactoring and heterologous overexpression strategy showcased in this study is potentially applicable to other ribosomally synthesized and post-translationally modified peptide BGCs from Firmicutes, unlocking the genetic potential of Firmicutes for producing peptide natural products.
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影响因子：
62.1
作者：
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通讯作者：
van der Donk WA
影响因子：
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作者：
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van der Donk, Wilfred A.
DOI：
10.1073/pnas.1306101110
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影响因子：
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