Eliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA

Abstract Actinobacteria are among the most prolific sources of medically and agriculturally important compounds, derived from their biosynthetic gene clusters (BGCs) for specialized (secondary) pathways of metabolism. Genomics witnesses that the majority of actinobacterial BGCs are silent, most like...

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Autores principales:	Oleksandr Yushchuk, Iryna Ostash, Eva Mösker, Iryna Vlasiuk, Maksym Deneka, Christian Rückert, Tobias Busche, Victor Fedorenko, Jörn Kalinowski, Roderich D. Süssmuth, Bohdan Ostash
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Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/057a7057442146c8ad1690394f59b75a
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spelling	oai:doaj.org-article:057a7057442146c8ad1690394f59b75a2021-12-02T14:11:28ZEliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA10.1038/s41598-021-82934-62045-2322https://doaj.org/article/057a7057442146c8ad1690394f59b75a2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82934-6https://doaj.org/toc/2045-2322Abstract Actinobacteria are among the most prolific sources of medically and agriculturally important compounds, derived from their biosynthetic gene clusters (BGCs) for specialized (secondary) pathways of metabolism. Genomics witnesses that the majority of actinobacterial BGCs are silent, most likely due to their low or zero transcription. Much effort is put into the search for approaches towards activation of silent BGCs, as this is believed to revitalize the discovery of novel natural products. We hypothesized that the global transcriptional factor AdpA, due to its highly degenerate operator sequence, could be used to upregulate the expression of silent BGCs. Using Streptomyces cyanogenus S136 as a test case, we showed that plasmids expressing either full-length adpA or its DNA-binding domain led to significant changes in the metabolome. These were evident as changes in the accumulation of colored compounds, bioactivity, as well as the emergence of a new pattern of secondary metabolites as revealed by HPLC-ESI-mass spectrometry. We further focused on the most abundant secondary metabolite and identified it as the polyene antibiotic lucensomycin. Finally, we uncovered the entire gene cluster for lucensomycin biosynthesis (lcm), that remained elusive for five decades until now, and outlined an evidence-based scenario for its adpA-mediated activation.Oleksandr YushchukIryna OstashEva MöskerIryna VlasiukMaksym DenekaChristian RückertTobias BuscheVictor FedorenkoJörn KalinowskiRoderich D. SüssmuthBohdan OstashNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Oleksandr Yushchuk Iryna Ostash Eva Mösker Iryna Vlasiuk Maksym Deneka Christian Rückert Tobias Busche Victor Fedorenko Jörn Kalinowski Roderich D. Süssmuth Bohdan Ostash Eliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA
description	Abstract Actinobacteria are among the most prolific sources of medically and agriculturally important compounds, derived from their biosynthetic gene clusters (BGCs) for specialized (secondary) pathways of metabolism. Genomics witnesses that the majority of actinobacterial BGCs are silent, most likely due to their low or zero transcription. Much effort is put into the search for approaches towards activation of silent BGCs, as this is believed to revitalize the discovery of novel natural products. We hypothesized that the global transcriptional factor AdpA, due to its highly degenerate operator sequence, could be used to upregulate the expression of silent BGCs. Using Streptomyces cyanogenus S136 as a test case, we showed that plasmids expressing either full-length adpA or its DNA-binding domain led to significant changes in the metabolome. These were evident as changes in the accumulation of colored compounds, bioactivity, as well as the emergence of a new pattern of secondary metabolites as revealed by HPLC-ESI-mass spectrometry. We further focused on the most abundant secondary metabolite and identified it as the polyene antibiotic lucensomycin. Finally, we uncovered the entire gene cluster for lucensomycin biosynthesis (lcm), that remained elusive for five decades until now, and outlined an evidence-based scenario for its adpA-mediated activation.
format	article
author	Oleksandr Yushchuk Iryna Ostash Eva Mösker Iryna Vlasiuk Maksym Deneka Christian Rückert Tobias Busche Victor Fedorenko Jörn Kalinowski Roderich D. Süssmuth Bohdan Ostash
author_facet	Oleksandr Yushchuk Iryna Ostash Eva Mösker Iryna Vlasiuk Maksym Deneka Christian Rückert Tobias Busche Victor Fedorenko Jörn Kalinowski Roderich D. Süssmuth Bohdan Ostash
author_sort	Oleksandr Yushchuk
title	Eliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA
title_short	Eliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA
title_full	Eliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA
title_fullStr	Eliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA
title_full_unstemmed	Eliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA
title_sort	eliciting the silent lucensomycin biosynthetic pathway in streptomyces cyanogenus s136 via manipulation of the global regulatory gene adpa
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/057a7057442146c8ad1690394f59b75a
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Eliciting the silent lucensomycin biosynthetic pathway in Streptomyces cyanogenus S136 via manipulation of the global regulatory gene adpA

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