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  X-domain of peptide synthetases recruits oxygenases crucial for glycopeptide biosynthesis

Haslinger, K., Peschke, M., Brieke, C., Maximowitsch, E., & Cryle, M. (2015). X-domain of peptide synthetases recruits oxygenases crucial for glycopeptide biosynthesis. Nature, 521(7550), 105-109. doi:10.1038/nature14141.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-D024-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-A3D5-E
Genre: Journal Article

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Haslinger, Kristina1, Author              
Peschke, Madeleine1, Author              
Brieke, Clara1, Author              
Maximowitsch, Eglé1, Author              
Cryle, Max1, 2, Author              
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1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              
2Cytochrome P450, Max Planck Institute for Medical Research, Max Planck Society, Jahnstrasse 29, 69120 Heidelberg, DE, ou_1497697              

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 Abstract: Non-ribosomal peptide synthetase (NRPS) mega-enzyme complexes are modular assembly lines that are involved in the biosynthesis of numerous peptide metabolites independently of the ribosome. The multiple interactions between catalytic domains within the NRPS machinery are further complemented by additional interactions with external enzymes, particularly focused on the final peptide maturation process. An important class of NRPS metabolites that require extensive external modification of the NRPS-bound peptide are the glycopeptide antibiotics (GPAs), which include vancomycin and teicoplanin. These clinically relevant peptide antibiotics undergo cytochrome P450-catalysed oxidative crosslinking of aromatic side chains to achieve their final, active conformation. However, the mechanism underlying the recruitment of the cytochrome P450 oxygenases to the NRPS-bound peptide was previously unknown. Here we show, through in vitro studies, that the X-domain, a conserved domain of unknown function present in the final module of all GPA NRPS machineries, is responsible for the recruitment of oxygenases to the NRPS-bound peptide to perform the essential side-chain crosslinking. X-ray crystallography shows that the X-domain is structurally related to condensation domains, but that its amino acid substitutions render it catalytically inactive. We found that the X-domain recruits cytochrome P450 oxygenases to the NRPS and determined the interface by solving the structure of a P450-X-domain complex. Additionally, we demonstrated that the modification of peptide precursors by oxygenases in vitro-in particular the installation of the second crosslink in GPA biosynthesis-occurs only in the presence of the X-domain. Our results indicate that the presentation of peptidyl carrier protein (PCP)-bound substrates for oxidation in GPA biosynthesis requires the presence of the NRPS X-domain to ensure conversion of the precursor peptide into a mature aglycone, and that the carrier protein domain alone is not always sufficient to generate a competent substrate for external cytochrome P450 oxygenases

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Language(s): eng - English
 Dates: 2014-07-102014-12-052015-02-092015-05-07
 Publication Status: Published in print
 Pages: 17
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 Rev. Type: Peer
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Title: Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 521 (7550) Sequence Number: - Start / End Page: 105 - 109 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238