Letter abstract
Nature Chemical Biology 3, 657 - 662 (2007)
Published online: 9 September 2007 | doi:10.1038/nchembio.2007.28
Expanding the promiscuity of a natural-product glycosyltransferase by directed evolution
Gavin J Williams1, Changsheng Zhang1 & Jon S Thorson1
Natural products, many of which are decorated with essential sugar residues, continue to serve as a key platform for drug development1. Adding or changing sugars attached to such natural products can improve the parent compound's pharmacological properties, specificity at multiple levels2, and/or even the molecular mechanism of action3. 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.
- Laboratory for Biosynthetic Chemistry, Pharmaceutical Sciences Division, School of Pharmacy, National Cooperative Drug Discovery Program, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin 53705, USA.
Correspondence to: Jon S Thorson1 e-mail: jsthorson@pharmacy.wisc.edu
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