Inhibition of β-1,4-Glucan Biosynthesis by Deoxyglucose

Abstract

GDP-and UDP-deoxyglucose inhibit the incorporation of glucose from UDP-glucose into dolichyl phosphate glucose and dolichyl pyrophosphate oligosaccharides. GDP-deoxyglucose inhibits by competing with the physiological nucleotide sugars recently has it been shown in animal tissues that UDP-dGlc exhibits a different inhibition pattern: dGlc is not transferred to lipid-linked saccharides and thus inhibition cannot be reversed by Dol-P (5). It seems that UDP-dGlc inhibits the UDP-Glc:Dol-P glucosyltransferase.The chlorophytous alga Prototheca zopfii appears to be an interesting system to study the effect of dGlc as a glucose analog. The formation of lipid-linked sugars has been studied in this system. The lipid involved is indistinguishable from liver Dol-P (11), and Dol-P-Glc as well as Dol-PP-(Glc). are formed from UDP-Glc as sugar donor (13). The oligosaccharide moiety is then transferred from the lipid to a protein acceptor, and this step is inhibited by coumarin (15). The protein-oligosaccharide seems to be a primer for the formation ofcellulose using GDP-Glc as donor (13)(14)(15).In this paper, we present evidence of the inhibition produced by deoxyglucose derivatives, as glucose analog, on the formation of glucolipids, glucose-containing glycoproteins, and glucans. The effect of the analog is also compared with that produced by coumarin, a known inhibitor of cellulose formation (3, 9, 15). dGlc2 is an analog of glucose that inhibits the formation of glucan as well as an analog of mannose that blocks mannan synthesis in yeast (10,17). Protein glycosylation is also suppressed by dGlc (6,24,26). It is metabolized in different tissues to give rise to 2,23,25). It is likely that these nucleotide-deoxysugars, and not the free sugar, are the compounds responsible for the inhibition of those processes.In the case of glucan and mannan synthesis, the mechanism of inhibition of deoxyglucose is not clear. On the other hand, the inhibition of protein glycosylation by GDP-dGlc seems to be due to interference with the lipid-mediated mannosylation of glycoproteins. The analog can be transferred to Dol-P or to Dol-PPoligosaccharides. In the first case, GDP-dGlc competes with the physiological nucleotide-sugars for Dol-P, and this effect is overcome by the addition of the lipid (27). When dGlc is incorporated into lipid-oligosaccharides, no further elongation of the saccharide chain occurs, thus blocking the transfer of the completed oligosaccharide to the protein (6,7,23). In these examples, dGlc is an analog of mannose.