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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2017-06-01
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Online Access: | https://doi.org/10.1038/s41598-017-03308-5 |
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doaj-bc74afa0add84c29833f93ffbe2a2b0d2020-12-08T01:52:18ZengNature Publishing GroupScientific Reports2045-23222017-06-01711810.1038/s41598-017-03308-5Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean hostKeita Amagai0Haruo Ikeda1Junko Hashimoto2Ikuko Kozone3Miho Izumikawa4Fumitaka Kudo5Tadashi Eguchi6Takemichi Nakamura7Hiroyuki Osada8Shunji Takahashi9Kazuo Shin-ya10Technology Research Association for Next Generation Natural Products ChemistryKitasato Institute for Life Sciences, Kitasato UniversityJapan Biological Informatics ConsortiumJapan Biological Informatics ConsortiumJapan Biological Informatics ConsortiumDepartment of Chemistry, Tokyo Institute of TechnologyDepartment of Chemistry, Tokyo Institute of TechnologyRIKEN Center for Sustainable Resource Science, Molecular Structure Characterization UnitRIKEN Center for Sustainable Resource Science, Chemical Biology Research GroupRIKEN Center for Sustainable Resource ScienceNational Institute of Advanced Industrial Science and TechnologyAbstract 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.https://doi.org/10.1038/s41598-017-03308-5 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Keita Amagai Haruo Ikeda Junko Hashimoto Ikuko Kozone Miho Izumikawa Fumitaka Kudo Tadashi Eguchi Takemichi Nakamura Hiroyuki Osada Shunji Takahashi Kazuo Shin-ya |
spellingShingle |
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 Scientific Reports |
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 Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-06-01 |
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. |
url |
https://doi.org/10.1038/s41598-017-03308-5 |
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