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Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis
Nonribosomal peptide synthetases containing starter condensation domains direct the biosynthesis of nonribosomal lipopeptides, which generally exhibit wide bioactivities. The acyl chain has strong impacts on bioactivity and toxicity, but the lack of an in-depth understanding of starter condensation...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804268/ https://www.ncbi.nlm.nih.gov/pubmed/33436600 http://dx.doi.org/10.1038/s41467-020-20548-8 |
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author | Zhong, Lin Diao, Xiaotong Zhang, Na Li, Fengwei Zhou, Haibo Chen, Hanna Bai, Xianping Ren, Xintong Zhang, Youming Wu, Dalei Bian, Xiaoying |
author_facet | Zhong, Lin Diao, Xiaotong Zhang, Na Li, Fengwei Zhou, Haibo Chen, Hanna Bai, Xianping Ren, Xintong Zhang, Youming Wu, Dalei Bian, Xiaoying |
author_sort | Zhong, Lin |
collection | PubMed |
description | Nonribosomal peptide synthetases containing starter condensation domains direct the biosynthesis of nonribosomal lipopeptides, which generally exhibit wide bioactivities. The acyl chain has strong impacts on bioactivity and toxicity, but the lack of an in-depth understanding of starter condensation domain-mediated lipoinitiation limits the bioengineering of NRPSs to obtain novel derivatives with desired acyl chains. Here, we show that the acyl chains of the lipopeptides rhizomide, holrhizin, and glidobactin were modified by engineering the starter condensation domain, suggesting a workable approach to change the acyl chain. Based on the structure of the mutated starter condensation domain of rhizomide biosynthetic enzyme RzmA in complex with octanoyl-CoA and related point mutation experiments, we identify a set of residues responsible for the selectivity of substrate acyl chains and extend the acyl chains from acetyl to palmitoyl. Furthermore, we illustrate three possible conformational states of starter condensation domains during the reaction cycle of the lipoinitiation process. Our studies provide further insights into the mechanism of lipoinitiation and the engineering of nonribosomal peptide synthetases. |
format | Online Article Text |
id | pubmed-7804268 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78042682021-01-21 Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis Zhong, Lin Diao, Xiaotong Zhang, Na Li, Fengwei Zhou, Haibo Chen, Hanna Bai, Xianping Ren, Xintong Zhang, Youming Wu, Dalei Bian, Xiaoying Nat Commun Article Nonribosomal peptide synthetases containing starter condensation domains direct the biosynthesis of nonribosomal lipopeptides, which generally exhibit wide bioactivities. The acyl chain has strong impacts on bioactivity and toxicity, but the lack of an in-depth understanding of starter condensation domain-mediated lipoinitiation limits the bioengineering of NRPSs to obtain novel derivatives with desired acyl chains. Here, we show that the acyl chains of the lipopeptides rhizomide, holrhizin, and glidobactin were modified by engineering the starter condensation domain, suggesting a workable approach to change the acyl chain. Based on the structure of the mutated starter condensation domain of rhizomide biosynthetic enzyme RzmA in complex with octanoyl-CoA and related point mutation experiments, we identify a set of residues responsible for the selectivity of substrate acyl chains and extend the acyl chains from acetyl to palmitoyl. Furthermore, we illustrate three possible conformational states of starter condensation domains during the reaction cycle of the lipoinitiation process. Our studies provide further insights into the mechanism of lipoinitiation and the engineering of nonribosomal peptide synthetases. Nature Publishing Group UK 2021-01-12 /pmc/articles/PMC7804268/ /pubmed/33436600 http://dx.doi.org/10.1038/s41467-020-20548-8 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zhong, Lin Diao, Xiaotong Zhang, Na Li, Fengwei Zhou, Haibo Chen, Hanna Bai, Xianping Ren, Xintong Zhang, Youming Wu, Dalei Bian, Xiaoying Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis |
title | Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis |
title_full | Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis |
title_fullStr | Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis |
title_full_unstemmed | Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis |
title_short | Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis |
title_sort | engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804268/ https://www.ncbi.nlm.nih.gov/pubmed/33436600 http://dx.doi.org/10.1038/s41467-020-20548-8 |
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