Formation of 2-Deoxyglucose-Containing Lipid-Linked Oligosaccharides. Interference with Glycosylation of Glycoproteins

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Abstract
Crude membrane preparations from chick embryo cells catalyze the formation of dolichyl-di-N-acetylchitobiosyl diphosphate [Dol-PP-(GlcNAc)2] from UDP N-acetylglucosamine (UDP-GlcNAc). The formation of this glycolipid was stimulated by exogenous dolichyl phosphate and inhibited by tunicamycin. Adding GDP-mannose to the cell-free system containing Dol-PP-(GlcNAc)2 by preincubation led to the formation of a lipid-linked oligosaccharide, containing 8-9 sugar residues. The formation of lipid-linked oligosaccharides was inhibited by GDP-2-deoxy-D-glucose (GDP-dGlc): in this case Dol-PP-(GlcNAc)2-dGlc accumulated. Subsequent additions of mannosyl residues to this trisaccharide-lipid to form lipid-linked oligosaccharides were not possible. Concomitantly the glycosylation of proteins was blocked. Partially inhibitory conditions were obtained by adding both GDP-dGlc and GDP-Man with an excess of GDP-dGlc. Glycosylation of proteins was observed but the glycopeptides did not contain 2-deoxyglucosyl residues. 2-Deoxyglucose-containing glycolipids accumulated. The main glycolipid formed under these conditions was Dol-PP-(GlcNAc)2-Man-dGlc. Lipid-linked oligosaccharides containing 2-deoxyglucose were formed under these conditions, although in small amounts, but were not transferred to protein. The molecular basis of the inhibitory action of 2-deoxyglucose on glycosylation of protein is the incorporation of 2-deoxyglucosyl residues during early phases of the biosynthesis of the lipid-linked oligosaccharides.

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