Hemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type I polyketide synthase

Abstract Engineering polyketide synthases is one of the most promising ways of producing a variety of polyketide derivatives. Exploring the undiscovered chemical space of this medicinally important class of middle molecular weight natural products will aid in the development of improved drugs in the...

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Autores principales:	Kei Kudo, Takehiro Nishimura, Ikuko Kozone, Junko Hashimoto, Noritaka Kagaya, Hikaru Suenaga, Haruo Ikeda, Kazuo Shin-ya
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b2430429dc1949ffa90e4ad9492f1d0d
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spelling	oai:doaj.org-article:b2430429dc1949ffa90e4ad9492f1d0d2021-12-02T16:57:37ZHemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type I polyketide synthase10.1038/s41598-021-88583-z2045-2322https://doaj.org/article/b2430429dc1949ffa90e4ad9492f1d0d2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88583-zhttps://doaj.org/toc/2045-2322Abstract Engineering polyketide synthases is one of the most promising ways of producing a variety of polyketide derivatives. Exploring the undiscovered chemical space of this medicinally important class of middle molecular weight natural products will aid in the development of improved drugs in the future. In previous work, we established methodology designated ‘module editing’ to precisely manipulate polyketide synthase genes cloned in a bacterial artificial chromosome. Here, in the course of investigating the engineering capacity of the rapamycin PKS, novel rapamycin derivatives 1–4, which lack the hemiacetal moiety, were produced through the heterologous expression of engineered variants of the rapamycin PKS. Three kinds of module deletions in the polyketide synthase RapC were designed, and the genetically engineered vectors were prepared by the in vitro module editing technique. Streptomyces avermitilis SUKA34 transformed with these edited PKSs produced new rapamycin derivatives. The planar structures of 1–4 established based on 1D and 2D NMR, ESI–TOF–MS and UV spectra revealed that 2 and 3 had skeletons well-matched to the designs, but 1 and 4 did not. The observations provide important insights into the mechanisms of the later steps of rapamycin skeletal formation as well as the ketone-forming oxygenase RapJ.Kei KudoTakehiro NishimuraIkuko KozoneJunko HashimotoNoritaka KagayaHikaru SuenagaHaruo IkedaKazuo Shin-yaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kei Kudo Takehiro Nishimura Ikuko Kozone Junko Hashimoto Noritaka Kagaya Hikaru Suenaga Haruo Ikeda Kazuo Shin-ya Hemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type I polyketide synthase
description	Abstract Engineering polyketide synthases is one of the most promising ways of producing a variety of polyketide derivatives. Exploring the undiscovered chemical space of this medicinally important class of middle molecular weight natural products will aid in the development of improved drugs in the future. In previous work, we established methodology designated ‘module editing’ to precisely manipulate polyketide synthase genes cloned in a bacterial artificial chromosome. Here, in the course of investigating the engineering capacity of the rapamycin PKS, novel rapamycin derivatives 1–4, which lack the hemiacetal moiety, were produced through the heterologous expression of engineered variants of the rapamycin PKS. Three kinds of module deletions in the polyketide synthase RapC were designed, and the genetically engineered vectors were prepared by the in vitro module editing technique. Streptomyces avermitilis SUKA34 transformed with these edited PKSs produced new rapamycin derivatives. The planar structures of 1–4 established based on 1D and 2D NMR, ESI–TOF–MS and UV spectra revealed that 2 and 3 had skeletons well-matched to the designs, but 1 and 4 did not. The observations provide important insights into the mechanisms of the later steps of rapamycin skeletal formation as well as the ketone-forming oxygenase RapJ.
format	article
author	Kei Kudo Takehiro Nishimura Ikuko Kozone Junko Hashimoto Noritaka Kagaya Hikaru Suenaga Haruo Ikeda Kazuo Shin-ya
author_facet	Kei Kudo Takehiro Nishimura Ikuko Kozone Junko Hashimoto Noritaka Kagaya Hikaru Suenaga Haruo Ikeda Kazuo Shin-ya
author_sort	Kei Kudo
title	Hemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type I polyketide synthase
title_short	Hemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type I polyketide synthase
title_full	Hemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type I polyketide synthase
title_fullStr	Hemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type I polyketide synthase
title_full_unstemmed	Hemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type I polyketide synthase
title_sort	hemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type i polyketide synthase
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b2430429dc1949ffa90e4ad9492f1d0d
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Hemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type I polyketide synthase

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