Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing.
Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing.
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Australine，一种吡咯里西啶生物碱，可抑制淀粉葡萄糖苷酶和糖蛋白加工。
DOI：
10.1021/bi00431a010
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发表时间：
1989
期刊：
影响因子：
2.9
通讯作者：
Elbein,AD
中科院分区：
文献类型：
--
作者：
Tropea,JE;Molyneux,RJ;Kaushal,GP;Pan,YT;Mitchell,M;Elbein,AD
Joseph E. Tropea,**· 1 Russell J. Molyneux, 5 G. P. Kaushal, 1 YT Pan, 1 Michael Mitchell, 1 和 Alan D. Elbein1 德克萨斯大学健康科学中心生物化学系，德克萨斯州圣安东尼奥市 78284-7760，以及美国农业部农业研究服务中心西部地区研究中心，伯克利，加利福尼亚州 94710 8 月 10 日收到， 1988；修订稿于 1988 年 10 月 21 日收到 摘要：Australine [(1/?, 2/?, 3/?, 75', 7aJ?)-3-(羟甲基)-1,2,7-三羟基吡咯里西啶]是一种多羟基化吡咯里西啶生物碱，从澳大利亚栗子种子中分离出来，并通过 NMR 和X 射线衍射分析 [Molyneux 等人 (1988) J. Nat.产品（正在印刷中）]。由于苦马豆碱和卡坦精胺是抑制特定糖苷酶的多羟基化吲哚里西啶生物碱，因此我们针对多种外切糖苷酶测试了 australine，以确定它是否会抑制这些酶中的任何一种。该生物碱被证明是 α-葡萄糖苷酶淀粉葡萄糖苷酶的良好抑制剂（在 5.8 µ 处抑制 50%），但它不抑制 0-葡萄糖苷酶、α-或/3-甘露糖苷酶或 α-或/3-半乳糖苷酶。淀粉葡萄糖苷酶的抑制具有竞争性。 Australine 还抑制糖蛋白加工酶葡萄糖苷酶 I，但对葡萄糖苷酶 II 仅具有轻微的活性。当与培养细胞一起孵育时，这种生物碱抑制糖苷酶 I 步骤中的糖蛋白加工，并导致糖蛋白与 Glc3Man7_9 (GlcNAc) 2-寡糖的积累。^ 在真核生物中发现的常见糖蛋白类型中，无论是细胞相关蛋白还是分泌蛋白，都是具有 N 连接或天冬酰胺连接寡糖的糖蛋白 (Kornfeld & Kornfeld， 1976；瓦格和巴尔，1981）。这些分子寡糖部分的生物合成涉及一系列复杂的事件，从合成 Glc3Man9-(GlcNAc) 2-焦磷酸多醇中间体开始，并将该中间体的碳水化合物部分转移到新合成的多肽上的各种天冬酰胺残基上（Elbein，1979；Struck & Lennarz，1980；Kornfeld & Kornfeld，1985）。在这种寡糖转移到蛋白质上之后，新形成的糖蛋白经历了一系列修饰或“加工”反应，这些反应在内质网中开始，并随着糖蛋白通过高尔基体转运到最终目的地而继续（Turco & Robbins，1976；Grinna & Robbins，1979；Hubbard & Ivatt，
Joseph E. Tropea,**· 1 Russell J. Molyneux, 5 G. P. Kaushal, 1 YT Pan, 1 Michael Mitchell, 1 and Alan D. Elbein1 Department of Biochemistry, The University of Texas Health Science Center, San Antonio, Texas 78284-7760, and Western Regional Research Center, Agricultural Research Service, US Department of Agriculture, Berkeley, California 94710 Received August 10, 1988; Revised Manuscript Received October 21, 1988 abstract: Australine [(1/?, 2/?, 3/?, 75', 7aJ?)-3-(hydroxymethyl)-1, 2, 7-trihydroxypyrrolizidine] is a polyhydroxy lated pyrrolizidine alkaloid that was isolated from the seeds of the Australian tree Castanospermum australe and characterized by NMR and X-ray diffraction analysis [Molyneux et al.(1988) J. Nat. Prod.(in press)]. Since swainsonine and catanospermine are polyhydroxylated indolizidine alkaloids that inhibit specific glycosidases, we tested australine against a variety of exoglycosidases to determine whether it would inhibit any of these enzymes. This alkaloid proved to be a good inhibitor of the-glucosidase amyloglucosidase (50% inhibition at 5.8 µ), but it did not inhibit 0-glucosidase, a-or/3-mannosidase, or a-or/3-galactosidase. The inhibition of amyloglucosidase was of a competitive nature. Australine also inhibited the glycoprotein processing enzyme glucosidase I, but had only slight activity toward glucosidase II. When incubated with cultured cells, thisalkaloid inhibited glycoprotein processing at the glucosidase I step and caused the accumulation of glycoproteins with Glc3Man7_9 (GlcNAc) 2-oligosaccharides.^ Lmong the common types of glycoproteins that are found in eukaryotic organisms, both as cell-associated proteins and as secreted proteins, are those having N-linked or aspara-gine-linked oligosaccharides (Kornfeld & Kornfeld, 1976; Wagh & Bahl, 1981). The biosynthesis of the oligosaccharide portion of these molecules involves a complex sequence of events beginning with the synthesis of the Glc3Man9-(GlcNAc) 2-pyrophosphoryldolichol intermediate and the transfer of the carbohydrate portion of this intermediate to various asparagine residues on the newly synthesized poly-peptide (Elbein, 1979; Struck & Lennarz, 1980; Kornfeld & Kornfeld, 1985). Following the transfer of this oligosaccharide to the protein, the newly formed glycoprotein undergoes a number of modification or “processing” reactions which begin in the endoplasmic reticulum and continue as the glycoprotein is transported through the Golgi to its final destination (Turco & Robbins, 1976; Grinna & Robbins, 1979; Hubbard & Ivatt,