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Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent
Bibenzyls, a kind of important plant polyphenols, have attracted growing attention for their broad and remarkable pharmacological activities. However, due to the low abundance in nature, uncontrollable and environmentally unfriendly chemical synthesis processes, these compounds are not readily acces...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10149896/ https://www.ncbi.nlm.nih.gov/pubmed/37139416 http://dx.doi.org/10.1016/j.apsb.2022.10.007 |
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author | Liu, Yuyu Li, Xinnan Sui, Songyang Tang, Jingshu Chen, Dawei Kang, Yuying Xie, Kebo Liu, Jimei Lan, Jiaqi Wu, Lei Chen, Ridao Peng, Ying Dai, Jungui |
author_facet | Liu, Yuyu Li, Xinnan Sui, Songyang Tang, Jingshu Chen, Dawei Kang, Yuying Xie, Kebo Liu, Jimei Lan, Jiaqi Wu, Lei Chen, Ridao Peng, Ying Dai, Jungui |
author_sort | Liu, Yuyu |
collection | PubMed |
description | Bibenzyls, a kind of important plant polyphenols, have attracted growing attention for their broad and remarkable pharmacological activities. However, due to the low abundance in nature, uncontrollable and environmentally unfriendly chemical synthesis processes, these compounds are not readily accessible. Herein, one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes. Three types of efficiently post-modifying modular strains were engineered by employing methyltransferases, prenyltransferase, and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules. Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes. Especially, a prenylated bibenzyl derivative (12) was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke. RNA-seq, quantitative RT-PCR, and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor, mitochondria associated 3 (Aifm3), suggesting that Aifm3 might be a new target in ischemic stroke therapy. This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery. |
format | Online Article Text |
id | pubmed-10149896 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-101498962023-05-02 Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent Liu, Yuyu Li, Xinnan Sui, Songyang Tang, Jingshu Chen, Dawei Kang, Yuying Xie, Kebo Liu, Jimei Lan, Jiaqi Wu, Lei Chen, Ridao Peng, Ying Dai, Jungui Acta Pharm Sin B Original Article Bibenzyls, a kind of important plant polyphenols, have attracted growing attention for their broad and remarkable pharmacological activities. However, due to the low abundance in nature, uncontrollable and environmentally unfriendly chemical synthesis processes, these compounds are not readily accessible. Herein, one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes. Three types of efficiently post-modifying modular strains were engineered by employing methyltransferases, prenyltransferase, and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules. Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes. Especially, a prenylated bibenzyl derivative (12) was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke. RNA-seq, quantitative RT-PCR, and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor, mitochondria associated 3 (Aifm3), suggesting that Aifm3 might be a new target in ischemic stroke therapy. This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery. Elsevier 2023-04 2022-10-10 /pmc/articles/PMC10149896/ /pubmed/37139416 http://dx.doi.org/10.1016/j.apsb.2022.10.007 Text en © 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Liu, Yuyu Li, Xinnan Sui, Songyang Tang, Jingshu Chen, Dawei Kang, Yuying Xie, Kebo Liu, Jimei Lan, Jiaqi Wu, Lei Chen, Ridao Peng, Ying Dai, Jungui Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent |
title | Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent |
title_full | Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent |
title_fullStr | Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent |
title_full_unstemmed | Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent |
title_short | Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent |
title_sort | structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10149896/ https://www.ncbi.nlm.nih.gov/pubmed/37139416 http://dx.doi.org/10.1016/j.apsb.2022.10.007 |
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