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  Design and synthesis of peptide inhibitor conjugates as probes of the Cytochrome P450s from glycopeptide antibiotic biosynthesis

Brieke, C., Maier, T., Schröter, M., & Cryle, M. J. (2015). Design and synthesis of peptide inhibitor conjugates as probes of the Cytochrome P450s from glycopeptide antibiotic biosynthesis. MedChemComm, 7, 132-140. doi:10.1039/C5MD00332F.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-228A-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-228B-8
Genre: Journal Article

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 Creators:
Brieke, Clara1, Author              
Maier, Theresa, Author
Schröter, Martin, Author
Cryle, Max J.1, Author              
Affiliations:
1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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 Abstract: The glycopeptide antibiotics are important clinical antibiotics that are currently employed against serious Gram-positive bacterial infections. Their chemical complexity means that their production is reliant upon the natural biosynthesis pathway, of which the key steps are the synthesis and side chain cyclisation of the peptide backbone. These processes rely upon a non-ribosomal peptide synthetase (NRPS) and several Cytochrome P450 enzymes that interact with the NRPS-bound peptide to generate the active aglycone. These P450 catalysts, known as Oxy enzymes, are crucial for the biosynthesis and yet the nature of their interactions with substrate peptides remains poorly understood. In this work, we have developed a range of synthetic inhibitor peptide substrates conjugated to an extended phosphopantetheine linker mimic and apply these to the characterisation of the first P450 from vancomycin biosynthesis, OxyBvan. These compounds display improved solubility and binding properties in comparison to isolated GPA precursor peptides and provide insights into the binding of such peptides to the P450 active site. These probes are applicable to the characterisation of other P450s from related biosynthetic machineries and are promising candidates for co-crystallisation with the Oxy enzymes.

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Language(s): eng - English
 Dates: 2015-08-072015-09-242015-09-252015
 Publication Status: Published in print
 Pages: 9
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 Rev. Type: Peer
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Title: MedChemComm
Source Genre: Journal
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Publ. Info: European Federation for Medicinal Chemistry (EFMC)
Pages: - Volume / Issue: 7 Sequence Number: - Start / End Page: 132 - 140 Identifier: ISSN: 2040-2503