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  More than just recruitment: the X-domain influences catalysis of the first phenolic coupling reaction in A47934 biosynthesis by Cytochrome P450 StaH

Ulrich, V., Peschke, M., Brieke, C., & Cryle, M. (2016). More than just recruitment: the X-domain influences catalysis of the first phenolic coupling reaction in A47934 biosynthesis by Cytochrome P450 StaH. Molecular BioSystems, 12(10), 2992-3004. doi:10.1039/C6MB00373G.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-002C-B62A-1 Version Permalink: https://hdl.handle.net/11858/00-001M-0000-002C-B62B-0
Genre: Journal Article

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 Creators:
Ulrich, Veronika1, Author           
Peschke, Madeleine1, Author           
Brieke, Clara1, Author           
Cryle, Max1, Author           
Affiliations:
1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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 Abstract: Glycopeptide antibiotic biosynthesis involves a complex cascade of reactions centred on a non-ribosomal peptide synthetase and modifiying proteins acting in trans, such as Cytochrome P450 enzymes. These P450s are responsible for cyclisation of the peptide via cross-linking aromatic amino acid side chains, which are a hallmark of the glycopeptide antibiotics. Here, we analysed the first cyclisation reaction in the biosynthesis of the glycopeptide antibiotic A47934. Our results demonstrate that the P450 StaH is recruited to the NRPS machinery through interaction with the X-domain present in the last A47934 NRPS module. We determined the crystal structure of StaH and showed that it is responsible for the first cyclisation in A47934 biosynthesis and additionally exhibits flexible substrate specificity. Our results further point out that the X-domain has an impact on the efficiency of the in vitro cyclisation reaction: hybrid PCP-X constructs obtained by domain exchange between A47934 and teicoplanin biosynthesis NRPS modules reveal that the X-domain from A47934 leads to decreased P450 activity and alternate stereochemical preference for the substrate peptide. We determined that a tight interaction between StaH and the A47934 X-domain correlates with decreased in vitro P450 activity: this highlights the need for glycopeptide antibiotic cyclisation to be a dynamic system, with an overly tight interaction interfering with substrate turnover in vitro.

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Language(s): eng - English
 Dates: 2016-05-132016-06-222016-08-012016-10-20
 Publication Status: Issued
 Pages: 14
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1039/C6MB00373G
URI: https://www.ncbi.nlm.nih.gov/pubmed/27477788
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Title: Molecular BioSystems
Source Genre: Journal
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Publ. Info: Cambridge, UK : Royal Society of Chemistry
Pages: - Volume / Issue: 12 (10) Sequence Number: - Start / End Page: 2992 - 3004 Identifier: ISSN: 1742-206X
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000023020