Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host

Abstract Telomestatin, a strong telomerase inhibitor with G-quadruplex stabilizing activity, is a potential therapeutic agent for treating cancers. Difficulties in isolating telomestatin from microbial cultures and in chemical synthesis are bottlenecks impeding the wider use. Therefore, improvement...

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Autores principales:	Keita Amagai, Haruo Ikeda, Junko Hashimoto, Ikuko Kozone, Miho Izumikawa, Fumitaka Kudo, Tadashi Eguchi, Takemichi Nakamura, Hiroyuki Osada, Shunji Takahashi, Kazuo Shin-ya
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bc74afa0add84c29833f93ffbe2a2b0d
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spelling	oai:doaj.org-article:bc74afa0add84c29833f93ffbe2a2b0d2021-12-02T11:53:12ZIdentification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host10.1038/s41598-017-03308-52045-2322https://doaj.org/article/bc74afa0add84c29833f93ffbe2a2b0d2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03308-5https://doaj.org/toc/2045-2322Abstract Telomestatin, a strong telomerase inhibitor with G-quadruplex stabilizing activity, is a potential therapeutic agent for treating cancers. Difficulties in isolating telomestatin from microbial cultures and in chemical synthesis are bottlenecks impeding the wider use. Therefore, improvement in telomestatin production and structural diversification are required for further utilization and application. Here, we discovered the gene cluster responsible for telomestatin biosynthesis, and achieved production of telomestatin by heterologous expression of this cluster in the engineered Streptomyces avermitilis SUKA strain. Utilization of an optimal promoter was essential for successful production. Gene disruption studies revealed that the tlsB, tlsC, and tlsO–T genes play key roles in telomestatin biosynthesis. Moreover, exchanging TlsC core peptide sequences resulted in the production of novel telomestatin derivatives. This study sheds light on the expansion of chemical diversity of natural peptide products for drug development.Keita AmagaiHaruo IkedaJunko HashimotoIkuko KozoneMiho IzumikawaFumitaka KudoTadashi EguchiTakemichi NakamuraHiroyuki OsadaShunji TakahashiKazuo Shin-yaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Keita Amagai Haruo Ikeda Junko Hashimoto Ikuko Kozone Miho Izumikawa Fumitaka Kudo Tadashi Eguchi Takemichi Nakamura Hiroyuki Osada Shunji Takahashi Kazuo Shin-ya Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host
description	Abstract Telomestatin, a strong telomerase inhibitor with G-quadruplex stabilizing activity, is a potential therapeutic agent for treating cancers. Difficulties in isolating telomestatin from microbial cultures and in chemical synthesis are bottlenecks impeding the wider use. Therefore, improvement in telomestatin production and structural diversification are required for further utilization and application. Here, we discovered the gene cluster responsible for telomestatin biosynthesis, and achieved production of telomestatin by heterologous expression of this cluster in the engineered Streptomyces avermitilis SUKA strain. Utilization of an optimal promoter was essential for successful production. Gene disruption studies revealed that the tlsB, tlsC, and tlsO–T genes play key roles in telomestatin biosynthesis. Moreover, exchanging TlsC core peptide sequences resulted in the production of novel telomestatin derivatives. This study sheds light on the expansion of chemical diversity of natural peptide products for drug development.
format	article
author	Keita Amagai Haruo Ikeda Junko Hashimoto Ikuko Kozone Miho Izumikawa Fumitaka Kudo Tadashi Eguchi Takemichi Nakamura Hiroyuki Osada Shunji Takahashi Kazuo Shin-ya
author_facet	Keita Amagai Haruo Ikeda Junko Hashimoto Ikuko Kozone Miho Izumikawa Fumitaka Kudo Tadashi Eguchi Takemichi Nakamura Hiroyuki Osada Shunji Takahashi Kazuo Shin-ya
author_sort	Keita Amagai
title	Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host
title_short	Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host
title_full	Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host
title_fullStr	Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host
title_full_unstemmed	Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host
title_sort	identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/bc74afa0add84c29833f93ffbe2a2b0d
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Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host

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