Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 27, Pages 8048-8052Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201802856
Keywords
antibiotics; biosynthesis; cytochrome P450 enzymes; OxyC; vancomycin
Categories
Funding
- National Institutes of Health [DP2-AI-124786]
- Burroughs Wellcome Fund
- Searle Scholars Program
- Eli Lilly-Edward C. Taylor Fellowship in Chemistry
Ask authors/readers for more resources
The bioactivity of vancomycin is enabled by three aromatic crosslinks, the biosynthesis of which has been an active area of investigation for two decades. Two cytochrome P450 enzymes, OxyB and OxyA, have been shown to introduce bisaryl ether linkages with the help of a so-called X-domain. The final crosslink, however, a biaryl bond thought to be installed by OxyC, has remained elusive. We report the invitro reconstitution of the OxyC reaction and formation of the first carbon-carbon crosslink in any glycopeptide antibiotic. Using a cascade sequence, in which the peptide substrate was incubated with the Oxy enzymes in turn, we completed the chemoenzymatic synthesis of a vancomycin aglycone variant. This approach was also used to generate a new analogue carrying a thioamide linkage at residue 4, a precursor to the amidine derivative, which is effective against vancomycin-resistant pathogens. Our results set the stage for creating therapeutic vancomycin derivatives by using the native metalloenzymes.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available