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Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products

Endophytic fungi are promising producers of bioactive small molecules. Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters, exhibited its strong ability to produce numbers of secondary metabolites. However, this strain mainly pro...

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Autores principales: Wei, Qian, Bai, Jian, Yan, Daojiang, Bao, Xiuqi, Li, Wenting, Liu, Bingyu, Zhang, Dan, Qi, Xiangbing, Yu, Dequan, Hu, Youcai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893140/
https://www.ncbi.nlm.nih.gov/pubmed/33643832
http://dx.doi.org/10.1016/j.apsb.2020.07.020
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author Wei, Qian
Bai, Jian
Yan, Daojiang
Bao, Xiuqi
Li, Wenting
Liu, Bingyu
Zhang, Dan
Qi, Xiangbing
Yu, Dequan
Hu, Youcai
author_facet Wei, Qian
Bai, Jian
Yan, Daojiang
Bao, Xiuqi
Li, Wenting
Liu, Bingyu
Zhang, Dan
Qi, Xiangbing
Yu, Dequan
Hu, Youcai
author_sort Wei, Qian
collection PubMed
description Endophytic fungi are promising producers of bioactive small molecules. Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters, exhibited its strong ability to produce numbers of secondary metabolites. However, this strain mainly produce rubratoxins alone with high yield in varied culture conditions, suggested most gene clusters are silent. Efforts for mining the cryptic gene clusters in P. dangeardii, including epigenetic regulation and one-strain-many-compounds (OSMAC) approach were failed probably due to the high yield of rubratoxins. A metabolic shunting strategy by deleting the key gene for rubratoxins biosynthesis combining with optimization of culture condition successfully activated multiple silent genes encoding for other polyketide synthases (PKSs), and led to the trace compounds detectable. As a result, a total of 23 new compounds including azaphilone monomers, dimers, trimers with unprecedented polycyclic bridged heterocycle and spiral structures, as well as siderophores were identified. Some compounds showed significant cytotoxicities, anti-inflammatory or antioxidant activities. The attractive dual PKSs gene clusters for azaphilones biosynthesis were mined by bioinformatic analysis and overexpression of a pathway specific transcription factor. Our work therefor provides an efficient approach to mine the chemical diversity of endophytic fungi.
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spelling pubmed-78931402021-02-25 Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products Wei, Qian Bai, Jian Yan, Daojiang Bao, Xiuqi Li, Wenting Liu, Bingyu Zhang, Dan Qi, Xiangbing Yu, Dequan Hu, Youcai Acta Pharm Sin B Original Article Endophytic fungi are promising producers of bioactive small molecules. Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters, exhibited its strong ability to produce numbers of secondary metabolites. However, this strain mainly produce rubratoxins alone with high yield in varied culture conditions, suggested most gene clusters are silent. Efforts for mining the cryptic gene clusters in P. dangeardii, including epigenetic regulation and one-strain-many-compounds (OSMAC) approach were failed probably due to the high yield of rubratoxins. A metabolic shunting strategy by deleting the key gene for rubratoxins biosynthesis combining with optimization of culture condition successfully activated multiple silent genes encoding for other polyketide synthases (PKSs), and led to the trace compounds detectable. As a result, a total of 23 new compounds including azaphilone monomers, dimers, trimers with unprecedented polycyclic bridged heterocycle and spiral structures, as well as siderophores were identified. Some compounds showed significant cytotoxicities, anti-inflammatory or antioxidant activities. The attractive dual PKSs gene clusters for azaphilones biosynthesis were mined by bioinformatic analysis and overexpression of a pathway specific transcription factor. Our work therefor provides an efficient approach to mine the chemical diversity of endophytic fungi. Elsevier 2021-02 2020-08-05 /pmc/articles/PMC7893140/ /pubmed/33643832 http://dx.doi.org/10.1016/j.apsb.2020.07.020 Text en © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. http://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
Wei, Qian
Bai, Jian
Yan, Daojiang
Bao, Xiuqi
Li, Wenting
Liu, Bingyu
Zhang, Dan
Qi, Xiangbing
Yu, Dequan
Hu, Youcai
Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products
title Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products
title_full Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products
title_fullStr Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products
title_full_unstemmed Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products
title_short Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products
title_sort genome mining combined metabolic shunting and osmac strategy of an endophytic fungus leads to the production of diverse natural products
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893140/
https://www.ncbi.nlm.nih.gov/pubmed/33643832
http://dx.doi.org/10.1016/j.apsb.2020.07.020
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