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  Understanding the early stages of peptide formation during the biosynthesis of teicoplanin and related glycopeptide antibiotics

Kaniusaite, M., Tailhades, J., Kittilä, T., Fage, C. D., A., R. J., Goode, et al. (2020). Understanding the early stages of peptide formation during the biosynthesis of teicoplanin and related glycopeptide antibiotics. The FEBS Journal, 1-48. doi:10.1111/febs.15350.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-5975-3 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-5976-2
Genre: Journal Article

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FEBSJ_epub_2020_350.pdf (Preprint), 9MB
 
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 Creators:
Kaniusaite, Milda, Author
Tailhades, Julien, Author
Kittilä, Tiia1, Author              
Fage, Christopher D., Author
A., Robert J., Author
Goode, Author
Schittenhelm, Ralf B., Author
Cryle, Max J., Author
Affiliations:
1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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Free keywords: Glycopeptide antibiotics ; non‐ribosomal peptide synthetase ; teicoplanin ; biosynthesis ; epimerisation
 Abstract: The biosynthesis of the glycopeptide antibiotics (GPAs) demonstrates the exceptional ability of non‐ribosomal peptide synthesis to generate diverse and complex structures from an expanded array of amino acid precursors. Whilst the heptapeptide cores of GPAs share a conserved C‐terminus, including the aromatic residues involved crosslinking and that are essential for the antibiotic activity of GPAs, most structural diversity is found within the N‐terminus of the peptide. Furthermore, the origin of the (D)‐stereochemistry of residue 1 of all GPAs is currently unclear, despite its importance for antibiotic activity. Given these important features, we have now reconstituted modules 1‐4 of the non‐ribosomal peptide synthetase (NRPS) assembly lines that synthesise the clinically‐relevant type IV GPA teicoplanin and the related compound A40926. Our results show that important roles in amino acid modification during the NRPS‐mediated biosynthesis of GPAs can be ascribed to the actions of condensation domains present within these modules, including the incorporation of (D)‐amino acids at position 1 of the peptide. Our results also indicate that hybrid NRPS assembly lines can be generated in a facile manner by mixing NRPS proteins from different systems, and that uncoupling of peptide formation due to different rates of activity seen for NRPS modules can be controlled by varying the ratio of NRPS modules. Taken together, this indicates that NRPS assembly lines function as dynamic peptide assembly lines and not static megaenzyme complexes, which has significant implications for biosynthetic redesign of these important biosynthetic systems.

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Language(s): eng - English
 Dates: 2020-04-202019-12-042020-04-282020-05-02
 Publication Status: Published online
 Pages: 48
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1111/febs.15350
 Degree: -

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Title: The FEBS Journal
  Other : The Federation if European Biochemical Societies Journal
Source Genre: Journal
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Publ. Info: Wiley-Blackwell
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: 1 - 48 Identifier: ISSN: 1742-464X
CoNE: https://pure.mpg.de/cone/journals/resource/954925398485