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Article: Refactoring and Heterologous Expression of Class III Lanthipeptide Biosynthetic Gene Clusters Lead to the Discovery of N,N-Dimethylated Lantibiotics from Firmicutes

TitleRefactoring and Heterologous Expression of Class III Lanthipeptide Biosynthetic Gene Clusters Lead to the Discovery of N,N-Dimethylated Lantibiotics from Firmicutes
Authors
Issue Date9-Mar-2023
PublisherAmerican Chemical Society
Citation
ACS Chemical Biology, 2023, v. 18, n. 3, p. 508-517 How to Cite?
Abstract

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 cluster (BGC) distribution has revealed their high abundance in the phylum Firmicutes. Many of these clusters also feature methyltransferase (MT) 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 MT-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 MT 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.


Persistent Identifierhttp://hdl.handle.net/10722/331312
ISSN
2023 Impact Factor: 3.5
2023 SCImago Journal Rankings: 1.344
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorXue, D-
dc.contributor.authorShang, Z-
dc.contributor.authorOlder, EA-
dc.contributor.authorZhong, Z-
dc.contributor.authorPulliam, C-
dc.contributor.authorPeter, K-
dc.contributor.authorNagarkatti, M-
dc.contributor.authorNagarkatti, P-
dc.contributor.authorLi, YX-
dc.contributor.authorLi, J-
dc.date.accessioned2023-09-21T06:54:36Z-
dc.date.available2023-09-21T06:54:36Z-
dc.date.issued2023-03-09-
dc.identifier.citationACS Chemical Biology, 2023, v. 18, n. 3, p. 508-517-
dc.identifier.issn1554-8929-
dc.identifier.urihttp://hdl.handle.net/10722/331312-
dc.description.abstract<p></p><p>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 cluster (BGC) distribution has revealed their high abundance in the phylum Firmicutes. Many of these clusters also feature methyltransferase (MT) 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 MT-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 MT 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.<br></p>-
dc.languageeng-
dc.publisherAmerican Chemical Society-
dc.relation.ispartofACS Chemical Biology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleRefactoring and Heterologous Expression of Class III Lanthipeptide Biosynthetic Gene Clusters Lead to the Discovery of N,N-Dimethylated Lantibiotics from Firmicutes-
dc.typeArticle-
dc.identifier.doi10.1021/acschembio.2c00849-
dc.identifier.scopuseid_2-s2.0-85149789317-
dc.identifier.volume18-
dc.identifier.issue3-
dc.identifier.spage508-
dc.identifier.epage517-
dc.identifier.eissn1554-8937-
dc.identifier.isiWOS:000948779300001-
dc.identifier.issnl1554-8929-

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