Platt F M, Neises G R, Karlsson G B, Dwek R A, Butters T D
Department of Biochemistry, University of Oxford, United Kingdom.
J Biol Chem. 1994 Oct 28;269(43):27108-14.
We have previously reported that the imino sugar N-butyldeoxynojirimycin (NB-DNJ) inhibits glycolipid biosynthesis, in addition to its known activity as an inhibitor of the N-linked oligosaccharide processing enzyme alpha-glucosidase I. In an attempt to dissociate these two activities and identify an inhibitor which was more selective for the glycolipid biosynthetic pathway, several imino sugars have been N-alkylated and tested for inhibitory activity. The galactose analogue N-butyldeoxygalactonojirimycin (NB-DGJ) was found to be a potent inhibitor of glycolipid biosynthesis but in contrast to NB-DNJ had no effect on the maturation of N-linked oligosaccharides or on lysosomal glucocerebrosidase. The effect of increasing N-alkyl chain length on glycolipid inhibition was investigated. Nonalkylated DGJ, the N-methyl and N-ethyl derivatives, were noninhibitory. However, N-propylation resulted in partial inhibition while the N-butyl and N-hexyl derivatives resulted in maximal inhibition. Increasing alkyl chain length also resulted in increased potency of glucosyltransferase inhibition. In an in vitro Gaucher's disease model NB-DGJ was as effective as NB-DNJ in preventing glycolipid storage and may represent a more selective potential therapeutic agent than NB-DNJ for the management of this and other glycosphingolipidoses.
我们之前报道过，亚氨基糖N-丁基脱氧野尻霉素（NB-DNJ）除了作为N-连接寡糖加工酶α-葡萄糖苷酶I的抑制剂具有已知活性外，还能抑制糖脂生物合成。为了分离这两种活性并鉴定出对糖脂生物合成途径更具选择性的抑制剂，我们对几种亚氨基糖进行了N-烷基化，并测试了它们的抑制活性。发现半乳糖类似物N-丁基脱氧半乳糖野尻霉素（NB-DGJ）是糖脂生物合成的有效抑制剂，但与NB-DNJ不同的是，它对N-连接寡糖的成熟或溶酶体葡萄糖脑苷脂酶没有影响。研究了增加N-烷基链长度对糖脂抑制的影响。未烷基化的DGJ、N-甲基和N-乙基衍生物没有抑制作用。然而，N-丙基化导致部分抑制，而N-丁基和N-己基衍生物导致最大抑制。增加烷基链长度也导致葡萄糖基转移酶抑制效力增加。在体外戈谢病模型中，NB-DGJ在预防糖脂蓄积方面与NB-DNJ一样有效，并且对于戈谢病及其他糖鞘脂贮积症的治疗而言，它可能比NB-DNJ更具选择性，是一种潜在的治疗药物。
