INHIBITORS OF PROCESSING AND LYSOSOMAL GLYCOSIDASES

糖苷酶在哺乳动物细胞中至少在 几个容量。在一个能力，他们是必不可少的处理 细胞表面和分泌性糖蛋白的寡糖链。 这些加工反应是形成络合物所必需的 可作为许多细胞表面受体的糖蛋白类型 重要的生物分子或相互作用。以另一种身份， 糖苷酶对溶酶体的功能至关重要，并起到降解作用 各种复杂的碳水化合物，如蛋白多糖、糖脂和 糖蛋白。某些溶酶体糖苷酶缺失或改变 导致仓储疾病，如赫勒斯综合症或亨特斯综合症 粘多糖症，或Gauchers或Tay Sachs作为例子 黏液淤积症。最近，我们发现植物生物碱苦马豆素是 一种有效的糖蛋白加工抑制剂，当给予细胞时 培养，并防止形成正常的复杂寡糖。 其他工人发现这种化合物抑制了加工。 甘露糖苷酶II，并可能导致形成杂交型 低聚糖。苦马豆素还抑制溶酶体α-甘露糖苷酶和 会导致摄入它的动物出现阿尔法甘露糖症的症状。自.以来 苦马豆素是一种三羟基吲哚利定，看起来很可能是其他 这种化合物的立体异构体会抑制参与 糖蛋白加工或溶酶体功能。这些立体异构体会 是研究糖蛋白过程和引起 形成改变的糖蛋白，或者它们可能对 抑制溶酶体糖苷酶和模拟溶酶体储藏疾病。 我们最近的发现强化了这一观点，即一种四羟基化的 生物碱，藜芦碱，是一种有效的β-葡萄糖苷酶和 也是β-葡萄糖脑苷酶。因此，我们将合成苦马豆素和 它的各种立体异构体，并将测试这些合成的异构体 来看看哪些糖苷酶被抑制了。我们还将测试这些 几种哺乳动物细胞系统上的异构体，以确定它们对 糖蛋白加工。我们亦会完成有关的生物研究 苦马豆素和藜芦碱对糖蛋白抑制作用的研究 正在处理。这些研究将在细胞培养中进行。

Glycosidases have essential functions in mammalian cells in at least several capacities. In one capacity, they are essential for the processing of the oligosaccharide chain of cell surface and secretory glycoproteins. These processing reactions are necessary for the formation of the complex types of glycoproteins that may function as cell surface receptors for many important biological molecules or interactions. In another capacity, glycosidases are critical to lysosomal function and serve to degrade various complex carbohydrates such as proteoglycans, glycolipids and glycoproteins. Absence or alteration of certain lysosomal glycosidases leads to storage diseases such as Hurlers or Hunters syndromes as examples of mucopolysaccharidosis, or Gauchers or Tay Sachs as examples of mucolipodosis. Recently, we found that the plant alkaloid swainsonine was a potent inhibitor of glycoprotein processing when given to cells in culture, and prevented the formation of normal complex oligosaccharides. The compound was shown by other workers to inhibit the processing mannosidase II and probably results in the formation of a hybrid type of oligosaccharide. Swainsonine also inhibits lysosomal Alpha-mannosidase and causes symptoms of Alpha-mannosidosis in animals that ingest it. Since swainsonine is a trihydroxylated indolizidine, it seems likely that other stereoisomers of this compound would inhibit other glycosidases involved in glycoprotein processing or lysosomal function. These stereoisomers would be valuable tools for studying glycoprotein processing and causing the formation of altered glycoproteins, or they might be valuable for inhibiting lysosomal glycosidases and mimicing lysosomal storage diseases. This idea is strengthened by our recent finding that a tetrahydroxylated alkaloid, castanospermine, is a potent inhibitor of Beta-glucosidase and also of Beta-glucocerebrosidase. Thus, we will synthesize swainsonine and its various stereoisomers and will test these synthetic isomers on a number of glycosidases to see which ones are inhibited. We will also test these isomers on several mammalian cell systems to determine their effect on glycoprotein processing. We will also complete the biological studies on swainsonine and castanospermine to determine how they inhibit glycoprotein processing. These studies will be done in cell culture.