The impact of enzyme engineering upon natural product glycodiversification - PubMed (original) (raw)

Review

The impact of enzyme engineering upon natural product glycodiversification

Gavin J Williams et al. Curr Opin Chem Biol. 2008 Oct.

Abstract

Glycodiversification of natural products is an effective strategy for small molecule drug development. Recently, improved methods for chemo-enzymatic synthesis of glycosyl donors has spurred the characterization of natural product glycosyltransferases (GTs), revealing that the substrate specificity of many naturally occurring GTs as too stringent for use in glycodiversification. Protein engineering of natural product GTs has emerged as an attractive approach to overcome this limitation. This review highlights recent progress in the engineering/evolution of enzymes relevant to natural product glycodiversification with a particular focus upon GTs.

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Figures

Figure 1

Figure 1

Natural product glycosides and their therapeutic properties. Sugar moieties are highlighted blue.

Figure 2

Figure 2

Chemo-enzymatic glycorandomization. E1 represents a promiscuous anomeric sugar kinase, E2 represents a promiscuous sugar-1-phosphate nucleotidyltransferase, GT represents a promiscuous glycosyltransferase and the gray oval represents a complex natural product scaffold.

Figure 3

Figure 3

Engineering _N/O_-glucosylation activities in plant GTs. (a) Glycosylation of hydroxyl containing acceptors necessarily proceeds through proton abstraction whereas _N_-glycosyltransfer does not. 3,4-DCP, 3,4-dichlorophenol; 3,4-DCA, 3,4-dichloroaniline. (b) Catalytic efficiency of WT and mutant GTs toward _N_- and _O_-glucosyltransfer. WT BnUGT does not catalyze _N_-glucosyltransfer, 314N- F317Y displays considerable activity toward 3,4-DCA. The reciprocal mutations in UGT72B1 shifts the WT dual _N/O_-glucosyltransfer activity toward a more specific _O_-GT. (c) Active site of WT UGT72B1 showing the non-canonical interaction of His-19 with Ser-14. (d) Canonical geometry of the catalytic base in VvGT1 and (e) OleD (in this view, the substrate was excluded for clarity).

Figure 4

Figure 4

Diversity of acceptor substrates for evolved OleD variants.

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