期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 59, 期 27, 页码 10899-10903出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202003726
关键词
biocatalysis; biosynthesis; nonribosomal peptides; cytochrome P450 enzymes; glycopeptide antibiotics
资金
- Monash University
- National Health and Medical Research Council [APP1140619]
- Australian Research Council's Discovery Projects funding Scheme [DP170102220]
- EMBL Australia
- Australian Government
Glycopeptide antibiotics (GPAs) are important antibiotics that are highly challenging to synthesise due to their unique and heavily crosslinked structure. Given this, the synthetic production and diversification of this key compound class remains impractical. Furthermore, the possibility of biosynthetic reengineering of GPAs is not yet feasible since the selectivity of the biosynthetic crosslinking enzymes for altered substrates is largely unknown. We show that combining peptide synthesis with enzymatic cyclisation enables the formation of novel examples of GPAs and provides an indication of the utility of these crucial enzymes. By accessing the biosynthetic process in vitro, we identified peptide modifications that are enzymatically tolerated and can also reveal the mechanistic basis for substrate intolerance where present. Using this approach, we next specifically activated modified residues within GPAs for functionalisation at previously inaccessible positions, thereby offering the possibility of late-stage chemical functionalisation after GPA cyclisation is complete.
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