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Biosynthesis of a new skyllamycin in <i>Streptomyces nodosus</i>: a cytochrome P450 forms an epoxide in the cinnamoyl chain

Yuhao Song Orcid Logo, Jose A. Amaya, Vidhi C. Murarka Orcid Logo, Hugo Mendez, Mark Hogan Orcid Logo, Jimmy Muldoon Orcid Logo, Paul Evans Orcid Logo, Yannick Ortin Orcid Logo, Steven Kelly, David Lamb Orcid Logo, Thomas L. Poulos, Patrick Caffrey Orcid Logo

Organic and Biomolecular Chemistry, Volume: 22, Issue: 14, Pages: 2835 - 2843

Swansea University Authors: Steven Kelly, David Lamb Orcid Logo

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DOI (Published version): 10.1039/d4ob00178h

Abstract

Activation of a silent gene cluster in Streptomyces nodosus leads to synthesis of a cinnamoyl-containing non-ribosomal peptide (CCNP) that is related to skyllamycins. This novel CCNP was isolated and its structure was interrogated using mass spectrometry and nuclear magnetic resonance spectroscopy....

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Published in: Organic and Biomolecular Chemistry
ISSN: 1477-0520 1477-0539
Published: Royal Society of Chemistry (RSC) 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa66030
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spelling v2 66030 2024-04-10 Biosynthesis of a new skyllamycin in <i>Streptomyces nodosus</i>: a cytochrome P450 forms an epoxide in the cinnamoyl chain b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false 2024-04-10 Activation of a silent gene cluster in Streptomyces nodosus leads to synthesis of a cinnamoyl-containing non-ribosomal peptide (CCNP) that is related to skyllamycins. This novel CCNP was isolated and its structure was interrogated using mass spectrometry and nuclear magnetic resonance spectroscopy. The isolated compound is an oxidised skyllamycin A in which an additional oxygen atom is incorporated in the cinnamoyl side-chain in the form of an epoxide. The gene for the epoxide-forming cytochrome P450 was identified by targeted disruption. The enzyme was overproduced in Escherichia coli and a 1.43 Å high-resolution crystal structure was determined. This is the first crystal structure for a P450 that forms an epoxide in a substituted cinnamoyl chain of a lipopeptide. These results confirm the proposed functions of P450s encoded by biosynthetic gene clusters for other epoxidized CCNPs and will assist investigation of how epoxide stereochemistry is determined in these natural products. Journal Article Organic and Biomolecular Chemistry 22 14 2835 2843 Royal Society of Chemistry (RSC) 1477-0520 1477-0539 cytochrome P450; Streptomyces; skyllamycin; antibiotic; epoxidation 18 3 2024 2024-03-18 10.1039/d4ob00178h COLLEGE NANME COLLEGE CODE Swansea University Another institution paid the OA fee Y. S. was supported by a Ph. D. studentship from the -China Scholarship Council scheme. M. H. received a Ph. D. studentship from the Irish Research Council for Science Engineering and Technology (IRCSET). Mass spectrometry facilities were funded as part of the Comprehensive Molecular Analysis Platform (CMAP) initiative under the Science Foundation Ireland (SFI) Research Infrastructure Programme, reference 18/RI/5702, and supported by UCD School of Chemistry. P. E. gratefully acknowledges support from SFI (12/RC/2275_P2 and 16/RC/3889). Research at Swansea University was supported by the European Regional Development Fund/Welsh European Funding Office via the BEACON project (S. L. K.). The crystallographic work was supported by National Institute of Health Grants GM131920 (T. L. P.). 2024-05-22T11:41:18.0889000 2024-04-10T10:24:03.7761891 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Yuhao Song 0000-0002-3898-5293 1 Jose A. Amaya 2 Vidhi C. Murarka 0000-0002-3471-9211 3 Hugo Mendez 4 Mark Hogan 0000-0002-3136-3555 5 Jimmy Muldoon 0000-0002-2187-9478 6 Paul Evans 0000-0002-0584-876x 7 Yannick Ortin 0000-0001-7685-2558 8 Steven Kelly 9 David Lamb 0000-0001-5446-2997 10 Thomas L. Poulos 11 Patrick Caffrey 0000-0002-0132-2410 12 66030__30211__3d7ffe8f88664d95b0964c58c982e186.pdf 66030.pdf 2024-05-01T14:04:34.8793270 Output 1488230 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. true eng https://creativecommons.org/licenses/by-nc/4.0/
title Biosynthesis of a new skyllamycin in <i>Streptomyces nodosus</i>: a cytochrome P450 forms an epoxide in the cinnamoyl chain
spellingShingle Biosynthesis of a new skyllamycin in <i>Streptomyces nodosus</i>: a cytochrome P450 forms an epoxide in the cinnamoyl chain
Steven Kelly
David Lamb
title_short Biosynthesis of a new skyllamycin in <i>Streptomyces nodosus</i>: a cytochrome P450 forms an epoxide in the cinnamoyl chain
title_full Biosynthesis of a new skyllamycin in <i>Streptomyces nodosus</i>: a cytochrome P450 forms an epoxide in the cinnamoyl chain
title_fullStr Biosynthesis of a new skyllamycin in <i>Streptomyces nodosus</i>: a cytochrome P450 forms an epoxide in the cinnamoyl chain
title_full_unstemmed Biosynthesis of a new skyllamycin in <i>Streptomyces nodosus</i>: a cytochrome P450 forms an epoxide in the cinnamoyl chain
title_sort Biosynthesis of a new skyllamycin in <i>Streptomyces nodosus</i>: a cytochrome P450 forms an epoxide in the cinnamoyl chain
author_id_str_mv b17cebaf09b4d737b9378a3581e3de93
1dc64e55c2c28d107ef7c3db984cccd2
author_id_fullname_str_mv b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
1dc64e55c2c28d107ef7c3db984cccd2_***_David Lamb
author Steven Kelly
David Lamb
author2 Yuhao Song
Jose A. Amaya
Vidhi C. Murarka
Hugo Mendez
Mark Hogan
Jimmy Muldoon
Paul Evans
Yannick Ortin
Steven Kelly
David Lamb
Thomas L. Poulos
Patrick Caffrey
format Journal article
container_title Organic and Biomolecular Chemistry
container_volume 22
container_issue 14
container_start_page 2835
publishDate 2024
institution Swansea University
issn 1477-0520
1477-0539
doi_str_mv 10.1039/d4ob00178h
publisher Royal Society of Chemistry (RSC)
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description Activation of a silent gene cluster in Streptomyces nodosus leads to synthesis of a cinnamoyl-containing non-ribosomal peptide (CCNP) that is related to skyllamycins. This novel CCNP was isolated and its structure was interrogated using mass spectrometry and nuclear magnetic resonance spectroscopy. The isolated compound is an oxidised skyllamycin A in which an additional oxygen atom is incorporated in the cinnamoyl side-chain in the form of an epoxide. The gene for the epoxide-forming cytochrome P450 was identified by targeted disruption. The enzyme was overproduced in Escherichia coli and a 1.43 Å high-resolution crystal structure was determined. This is the first crystal structure for a P450 that forms an epoxide in a substituted cinnamoyl chain of a lipopeptide. These results confirm the proposed functions of P450s encoded by biosynthetic gene clusters for other epoxidized CCNPs and will assist investigation of how epoxide stereochemistry is determined in these natural products.
published_date 2024-03-18T11:41:17Z
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