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Biosynthesis of a new skyllamycin in <i>Streptomyces nodosus</i>: a cytochrome P450 forms an epoxide in the cinnamoyl chain
,
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
Organic and Biomolecular Chemistry, Volume: 22, Issue: 14, Pages: 2835 - 2843
Swansea University Authors:
Steven Kelly, David Lamb
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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....
| Published in: | Organic and Biomolecular Chemistry |
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| ISSN: | 1477-0520 1477-0539 |
| Published: |
Royal Society of Chemistry (RSC)
2024
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa66030 |
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| 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. 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. |
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| Keywords: |
cytochrome P450; Streptomyces; skyllamycin; antibiotic; epoxidation |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
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.). |
| Issue: |
14 |
| Start Page: |
2835 |
| End Page: |
2843 |