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The glycopeptide antibiotics are peptide-based natural products with impressive antibiotic function that derives from their unique three-dimensional structure. Biosynthesis of the glycopeptide antibiotics centres of the combination of peptide synthesis, mediated by a non-ribosomal peptide synthetase, and the crosslinking of aromatic side chains of the peptide, mediated by the action of a cascade of Cytochrome P450s. Here, we report the first example of  in vitro  activity of OxyE, which catalyses the F- O -G ring formation reaction in teicoplanin biosynthesis. OxyE was found to only act after an initial C- O -D crosslink is installed by OxyB and to require an interaction with the unique NRPS domain from glycopeptide antibiotic – the X-domain – in order to display catalytic activity. We could demonstrate that OxyE displays limited stereoselectivity for the peptide, which mirrors the results from OxyB-catalysed turnover and is in sharp contrast to OxyA. Furthermore, we show that activity of a three-enzyme cascade (OxyB/OxyA/OxyE) in generating tricyclic glycopeptide antibiotic peptides depends upon the order of addition of the OxyA and OxyE enzymes to the reaction. This work demonstrates that complex enzymatic cascades from glycopeptide antibiotic biosynthesis can be reconstituted  in vitro  and provides new insights into the biosynthesis of these important antibiotics.

F-O-G Ring Formation in Glycopeptide Antibiotic Biosynthesis is Catalysed by OxyE