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- Title
Expanding the promiscuity of a natural-product glycosyltransferase by directed evolution.
- Authors
Williams, Gavin J.; Changsheng Zhang; Thorson, Jon S.
- Abstract
Natural products, many of which are decorated with essential sugar residues, continue to serve as a key platform for drug development. Adding or changing sugars attached to such natural products can improve the parent compound's pharmacological properties, specificity at multiple levels, and/or even the molecular mechanism of action. Though some natural-product glycosyltransferases (GTs) are sufficiently promiscuous for use in altering these glycosylation patterns, the stringent specificity of others remains a limiting factor in natural-product diversification and highlights a need for general GT engineering and evolution platforms. Herein we report the use of a simple high-throughput screen based on a fluorescent surrogate acceptor substrate to expand the promiscuity of a natural-product GT via directed evolution. Cumulatively, this study presents variant GTs for the glycorandomization of a range of therapeutically important acceptors, including aminocoumarins, flavonoids and macrolides, and a potential template for engineering other natural-product GTs.
- Subjects
NATURAL products; DRUG development; PHARMACOLOGY; GLYCOSYLTRANSFERASES; MOLECULAR dynamics; GLYCOSYLATION
- Publication
Nature Chemical Biology, 2007, Vol 3, Issue 10, p657
- ISSN
1552-4450
- Publication type
Article
- DOI
10.1038/nchembio.2007.28