Synthesis and characterization of a new class of inhibitors of membrane-associated UDP-glycosyltransferases.

P Paul, T M Lutz, C Osborn, S Kyosseva, A D Elbein, H Towbin, A Radominska, R R Drake

文献索引：J. Biol. Chem. 268(17) , 12933-8, (1993)

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摘要

A new class of compounds designed to inhibit membrane-associated glycosyltransferases were synthesized and their biological activities were characterized in liver microsomes and human lymphoma cell lines. These inhibitors are composed of N-acyl phenylaminoalcohol derivatives linked to uridine via different spacers. One inhibitor, termed PP36 (5'-[[N-(2-decanoylamino-3-hydroxy-3-phenylpropyloxycarbonyl )-glycyl[amino]-5'-deoxyuridine) competitively inhibited the enzyme glucosyl phosphoryldolichol synthase (Glc-P-Dol synthase) in rat liver microsomes. In rat and human liver microsomes incubated with PP36 and photolabeled with [beta-32P]5-azido-UDP-Glc, Glc-P-Dol synthase was the only protein observed to have decreased photoincorporation. Two other inhibitors, PP37 (5'-O-[[(2-decanoylamino-3-hydroxy-3-phenyl- propyloxycarbonyl)amino]sulfonyl]uridine and PP55 (5'-O-[[(2-decanoylamino-3- phenylpropyloxycarbonyl)amino]sulfonyl]uridine), were also shown to be competitive inhibitors of Glc-P-Dol synthase activity and photolabeling. Activities of glycosyltransferases involved in glycosphingolipid biosynthesis were little affected by these compounds. Analysis of the effects of PP36, PP37, and PP55 on the incorporation of [3H] leucine and [14C]galactose into glycoprotein and glycolipid fractions from two human cell lines indicated the following: PP36 reduced incorporation into both fractions, PP37 was ineffective, and PP55 only decreased incorporation into glycolipids.