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Pure Appl. Chem., 2007, Vol. 79, No. 4, pp. 785-799

Manipulating nature's sugar biosynthetic machineries for glycodiversification of macrolides: Recent advances and future prospects

Christopher J. Thibodeaux and Hung-wen Liu

Division of Medicinal Chemistry, College of Pharmacy, Department of Chemistry and Biochemistry, and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA

Abstract: Changing the sugar structures and glycosylation patterns of natural products is an effective means of altering the biological activity of clinically useful drugs. Several recent strategies have provided researchers with the opportunity to manipulate sugar structures and to change the sugar moieties attached to these natural products via a biosynthetic approach. In this review, we explore the utility of contemporary in vivo and in vitro methods to achieve natural product glycodiversification. This study will focus on recent progress from our laboratory in elucidating the biosynthesis of D-desosamine, a deoxysugar component of many macrolide antibiotics, and will highlight how we have engineered the D-desosamine biosynthetic pathway in Streptomyces venezuelae through targeted disruption and heterologous expression of the sugar biosynthetic genes to generate a variety of new glycoforms. The in vitro exploitation of the substrate flexibility of the endogenous D-desosamine glycosyltransferase (GT) to generate many non-natural glycoforms will also be discussed. These experiments are compared with recent work from other research groups on the same topics. Finally, the significance of these studies for the future prospects of natural product glycodiversification is discussed.