Understanding the Glycopeptide Antibiotic Crosslinking Cascade: In Vitro Approaches Reveal the Details of a Complex Biosynthesis Pathway

Yongwei Zhao, Y. T.Candace Ho, Julien Tailhades, Max Cryle

Research output: Contribution to journalReview ArticleResearchpeer-review

Abstract

The glycopeptide antibiotics (GPAs) are a fascinating example of complex natural product biosynthesis, with the nonribosomal synthesis of the peptide core coupled to a cytochrome P450-mediated cyclisation cascade that crosslinks aromatic side chains within this peptide. Given that the challenges associated with the synthesis of GPAs stems from their highly crosslinked structure, there is great interest in understanding how biosynthesis accomplishes this challenging set of transformations. In this regard, the use of in vitro experiments has delivered important insights into this process, including the identification of the unique role of the X-domain as a platform for P450 recruitment. In this minireview, we present an analysis of the results of in vitro studies into the GPA cyclisation cascade that have demonstrated both the tolerances and limitations of this process for modified substrates, and in turn developed rules for the future reengineering of this important antibiotic class.

Original languageEnglish
Number of pages10
JournalChemBioChem
DOIs
Publication statusAccepted/In press - 21 Jul 2020

Keywords

  • biocatalysis
  • biosynthesis
  • cytochrome P450s
  • glycopeptide antibiotics
  • nonribosomal peptide synthesis

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