{"title":"PEARL-Catalyzed Peptide Bond Formation after Chain Reversal by Ureido-Forming Condensation Domains","authors":"Yue Yu, and , Wilfred A. van der Donk*, ","doi":"10.1021/acscentsci.4c00044","DOIUrl":null,"url":null,"abstract":"<p >A subset of nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) are encoded in their biosynthetic gene clusters (BGCs) with enzymes annotated as lantibiotic dehydratases. The functions of these putative lantibiotic dehydratases remain unknown. Here, we characterize an NRPS-PKS BGC with a putative lantibiotic dehydratase from the bacterium <i>Stackebrandtia nassauensis</i> (<i>sna</i>). Heterologous expression revealed several metabolites produced by the BGC, and the omission of selected biosynthetic enzymes revealed the biosynthetic pathway toward these compounds. The final product is a bisarginyl ureidopeptide with an enone electrophile. The putative lantibiotic dehydratase catalyzes peptide bond formation to a Thr that extends the peptide scaffold opposite to the NRPS and PKS biosynthetic direction. The condensation domain of the NRPS SnaA catalyzes the formation of a ureido group, and bioinformatics analysis revealed a distinct active site signature EHHXXHDG of ureido-generating condensation (C<sub>urea</sub>) domains. This work demonstrates that the annotated lantibiotic dehydratase serves as a separate amide bond-forming machinery in addition to the NRPS, and that the lantibiotic dehydratase enzyme family possesses diverse catalytic activities in the biosynthesis of both ribosomal and nonribosomal natural products.</p><p >The discovery of threopeptin reveals the function of the putative lantibiotic dehydratases in nonribosomal peptide (NRP) BGCs and enables the bioinformatic prediction of ureido-containing NRPs.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":null,"pages":null},"PeriodicalIF":12.7000,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c00044","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Central Science","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acscentsci.4c00044","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
A subset of nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) are encoded in their biosynthetic gene clusters (BGCs) with enzymes annotated as lantibiotic dehydratases. The functions of these putative lantibiotic dehydratases remain unknown. Here, we characterize an NRPS-PKS BGC with a putative lantibiotic dehydratase from the bacterium Stackebrandtia nassauensis (sna). Heterologous expression revealed several metabolites produced by the BGC, and the omission of selected biosynthetic enzymes revealed the biosynthetic pathway toward these compounds. The final product is a bisarginyl ureidopeptide with an enone electrophile. The putative lantibiotic dehydratase catalyzes peptide bond formation to a Thr that extends the peptide scaffold opposite to the NRPS and PKS biosynthetic direction. The condensation domain of the NRPS SnaA catalyzes the formation of a ureido group, and bioinformatics analysis revealed a distinct active site signature EHHXXHDG of ureido-generating condensation (Curea) domains. This work demonstrates that the annotated lantibiotic dehydratase serves as a separate amide bond-forming machinery in addition to the NRPS, and that the lantibiotic dehydratase enzyme family possesses diverse catalytic activities in the biosynthesis of both ribosomal and nonribosomal natural products.
The discovery of threopeptin reveals the function of the putative lantibiotic dehydratases in nonribosomal peptide (NRP) BGCs and enables the bioinformatic prediction of ureido-containing NRPs.
期刊介绍:
ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.