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

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 ofin vitroexperiments 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 ofin vitrostudies 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.

Automated summary

Researchers are intrigued by the complex biosynthesis of glycopeptide antibiotics, particularly the role of the X-domain in recruiting P450 enzymes. In vitro studies have provided insights into the tolerances and limitations of the GPA cyclisation cascade, paving the way for future reengineering of this important antibiotic class.