The biological importance of oligosaccharides was first recognized in the context of their role in metabolism and energy storage. During the past three decades, it has become apparent that complex oligosaccharides also regulate many of the fundamental processes occurring in a biological system. Of special interest are the oligosaccharides found on the surfaces of cells (Fig. 1), which guide their social behavior. Among many other responsibilities, oligosaccharides mediate cell-cell interactions, regulate the serum half-life of glycoproteins, and serve as specific li-gands for bacteria, viruses, and parasites [1].

Progress toward the elucidation of oligosaccharide function has historically been impeded by their structural complexity and heterogeneity on cells [2]. The biosynthesis of glycoconjugates is determined by various factors, including the relative abundance and specificity of glycosyltransferases (the enzymes that build oli-gosaccharides one saccharide at a time), the spatial localization of these enzymes, the availability of nucleotide sugar donors, and the nature of the underlying substrate. Collectively, these factors result in a diverse array of heterogeneous structures that are difficult to control by using conventional genetic and biochemical tools.

Considerable creativity has been exercised in the development of strategies for modulating oligosaccharide structures on cell surfaces in a well-defined fashion. For example, specific glycosidase and glycosyltransferase inhibitors [3-8] have provided insight into the biosynthesis of glycans as well as their roles in biological processes. Glycosyltransferases have been used to modify cell surface glycans by exogenous treatment [9-11]. Another approach, the subject of this chapter, is to intercept metabolic pathways with unnatural monosaccharide substrates. If incorporated into cell

Introduction Penicillin
Figure 1 The landscape of the surfaces of cells.

surface oligosaccharides, modified sugars can aid in the elucidation of biological function (Fig. 2). Alternatively, modified substrates might block biosynthetic enzymes, producing phenotypes similar to those induced by glycosyltransferase inhibitors. We summarize here the historical development of metabolic substrate engineering as a tool for glycobiology. This chapter focuses on the journey of carbohydrate precursors and synthetic carbohydrate analogs through the metabolic pathways of the cell and the information that can be gained from investigating such processes.

We begin with an overview of the structures of glycoconjugates on cell surfaces (for more comprehensive reviews, see Refs. 2, 12-14, and 24). Next, the pathways of monosaccharide interconversions inside the cell are summarized, providing a framework for opportunities in unnatural monosaccharide metabolism. Specific examples of modified sugars and their effects on cells are then presented. Finally, the biosynthetic pathway of sialic acid is discussed with respect to its utility for cell surface oligosaccharide engineering.

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