INHIBITORS OF OLIGOSACCHARIDE PROCESSING

Abstract

Most proteins present on the surface of eukaryotic cells and proteins secreted by them are glycoproteins. Glycoproteins, generally speaking, may contain asparagine- -linked (N-linked) or serine/threonine linked (0-linked) oligosaccharides. A given protein may contain either one or both types of oligosaccharides. Notwithstanding their common occurrence -glycoproteins are found in bacteria, yeasts and all higher eukaryotes- there is no consensus on the function of protein bound glycans. They are thought to be involved in protection against proteolysis and contribute to or modify the folding of the polypeptide backbone. Protein bound glycans are also thought to constitute signals for intracellular traffic of glycoproteins, and may participate in determining the specificity of interactions between receptors and ligands and the interactions between cells. In present-day biotechnology, the importance of protein bound carbohydrate is likely to come under close scrutiny. Products produced by genetic engineering are often derived from cells or organisms that do not normally produce these substances (e.g. interferon production in bacteria) yet are intended for use in clinical applications. It is therefore of paramount importance to determine what, if any, role is played by protein bound carbohydrate. Parameters such as half-life in vivo, interaction with receptors, immunogenicity and the like may all be affected. Surprisingly enough, the armamentarium available for modifying carbohydrates in a predictable and directed manner is scarce. Through detailed knowledge of glycan biosynthesis, opportunities may be created to fill this gap. This article deals with inhibitors of N-linked oligosaccharide processing. These substances, most of which were described only recently, show promise of allowing the manipulation of N-linked glycan structures in a rather precise manner, and hence might be useful in investigations on the function of carbohydrates. In order to describe the effects of these inhibitors in their proper context, a4 brief overview of N-linked glycan synthesis will be given. Subsequently, the literature on the enzymes involved in N-linked glycan processing will be reviewed in some detail. Since the effects of the inhibitors to be described need not be the same for each of the enzymes involved even if these enzymes have very similar substrate specificities, their description as possibly distinct targets for inhibition is called for. The inhibitors of oligosaccharide trimming themselves will then be described in detail. Finally, the concluding remarks will deal with some possible applications of N-linked glycan processing inhibitors.