Discovery of a novel analogue of FR901533 and the corresponding biosynthetic gene cluster from Streptosporangium roseum No. 79089

Xu, Fuchao; Liang, Yonghong; Ren, Jie; Wang, Siyuan; Zhan, Jixun

doi:10.1007/s00253-020-10765-y

Applied genetics and molecular biotechnology
Published: 07 July 2020

Discovery of a novel analogue of FR901533 and the corresponding biosynthetic gene cluster from Streptosporangium roseum No. 79089

Fuchao Xu¹,
Yonghong Liang^1,2,
Jie Ren¹,
Siyuan Wang¹ &
Jixun Zhan ORCID: orcid.org/0000-0003-0200-9183¹

Applied Microbiology and Biotechnology volume 104, pages 7131–7142 (2020)Cite this article

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Abstract

FR901533 (1, also known as WS79089B), WS79089A (2), and WS79089C (3) are polycyclic aromatic natural products with promising inhibitory activity to endothelin-converting enzymes. In this work, we isolated five tridecaketide products from Streptosporangium roseum No. 79089, including 1–3, benaphthamycin (4) and a novel FR901533 analogue (5). The structure of 5 was characterized based on spectroscopic data. Compared with the major product 2, the new compound 5 has an additional hydroxyl group at C-12 and an extra methyl group at the 13-OH. The configuration of C-19 of these compounds was determined to be R using Mosher’s method. A putative biosynthetic gene cluster for compounds 1–5 was discovered by analyzing the genome of S. roseum No. 79089. This 38.6-kb gene cluster contains 38 open reading frames, including a minimal polyketide synthase (wsaA-C), an aromatase (wsaD), three cyclases (wsaE, F, and W), and a series of tailoring enzymes such as monooxygenases (wsaO1-O7) and methyltransferases (wsaM1 and M2). Disruption of the ketosynthase gene (wsaA) in this gene cluster abolished the production of 1–5, confirming that this gene cluster is indeed responsible for the biosynthesis of 1–5. A type II polyketide biosynthetic pathway was proposed for this group of natural endothelin-converting enzyme inhibitors.

Key points

• Five aromatic tridecaketides were isolated from Streptosporangium roseum No. 79089.

• A novel FR901533 analogue, 12-hydroxy-13-O-methyl-WS79089A, was characterized.

• The absolute configuration of C-19 of FR901533 and analogues was determined.

• The biosynthetic gene cluster of FR901533 and analogues was discovered.

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Funding

The Bruker Avance III HD Ascend-500 NMR instrument used in this research was funded by the National Science Foundation Award CHE–1429195.

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Affiliations

Department of Biological Engineering, Utah State University, 4105 Old Main Hill, Logan, UT, 84322-4105, USA
Fuchao Xu, Yonghong Liang, Jie Ren, Siyuan Wang & Jixun Zhan
Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, Jiangxi, China
Yonghong Liang

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Fuchao Xu
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Yonghong Liang
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Jie Ren
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Siyuan Wang
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Jixun Zhan
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Contributions

FX and JZ conceived and designed research. FX, YL, JR, and SW conducted experiments. FX, YL, JR, SW, and JZ analyzed data. FX and JZ wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Jixun Zhan.

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Xu, F., Liang, Y., Ren, J. et al. Discovery of a novel analogue of FR901533 and the corresponding biosynthetic gene cluster from Streptosporangium roseum No. 79089. Appl Microbiol Biotechnol 104, 7131–7142 (2020). https://doi.org/10.1007/s00253-020-10765-y

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Received: 13 May 2020
Revised: 22 June 2020
Accepted: 30 June 2020
Published: 07 July 2020
Issue Date: August 2020
DOI: https://doi.org/10.1007/s00253-020-10765-y

Keywords

FR901533
Endothelin-converting enzyme inhibitor
Polyketide biosynthesis
Streptosporangium roseum
Gene disruption