Despite their unparalleled catalytic prowess and environmental compatibility, enzymes have yet to see widespread application in synthetic chemistry. This lack of application and the resulting underuse of their enormous potential stems not only from a wariness about aqueous biological catalysis on the part of the typical synthetic chemist but also from limitations on enzyme applicability that arise from the high degree of substrate specificity possessed by most enzymes. This latter perceived limitation is being successfully challenged through rational protein engineering^{1, 2} and directed evolution efforts^{3, 4, 5, 6} to alter substrate specificity. However, such programs require considerable effort to establish. Here we report an alternative strategy for expanding the substrate specificity, and therefore the synthetic utility, of a given enzyme through a process of 'substrate engineering'. The attachment of a readily removable functional group to an alternative glycosyltransferase substrate induces a productive binding mode, facilitating rational control of substrate specificity and regioselectivity using wild-type enzymes.

1. Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada.
2. Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
3. Institute of Biological Sciences, National Research Council of Canada, Ottawa, Ontario K1A 0R6, Canada.
4. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.

Correspondence to: Stephen G Withers^1,4 Email: withers@chem.ubc.ca

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