NOVEL MANNOSIDASE INHIBITOR BLOCKING CONVERSION OF HIGH MANNOSE TO COMPLEX OLIGOSACCHARIDES
NOVEL MANNOSIDASE INHIBITOR BLOCKING CONVERSION OF HIGH MANNOSE TO COMPLEX OLIGOSACCHARIDES
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DOI：
10.1038/307755a0
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发表时间：
1984-01-01
期刊：
影响因子：
64.8
通讯作者：
PLOEGH, H
中科院分区：
文献类型：
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作者：
FUHRMANN, U;BAUSE, E;PLOEGH, H
许多分泌蛋白和膜蛋白是携带天冬酰胺连接（n -连接）寡糖的糖蛋白。n链聚糖有两种类型，分别称为高甘露糖型和复合体型。n链聚糖的生物合成是通过高甘露糖中间体进行的。具有（Glc）3(Man)9(GlcNAc)2组成的高甘露糖低聚糖从脂质载体转移到新生多肽链后，发生修剪反应。修剪葡萄糖苷酶可以定量地去除葡萄糖残基，甘露糖糖苷酶IA/B和II可以去除除三个甘露糖残基外的所有甘露糖残基。修剪后，末端糖如n -乙酰氨基葡萄糖、半乳糖、唾液酸和焦糖可以加入，并导致转化为复合物类型1的聚糖。由于缺乏合适的抑制剂，因此很难评估修剪反应对适当的细胞内运输的重要性，除了添加末端糖之外的修饰反应，或者作为糖蛋白加工的调节步骤。在这里，我们描述了1-脱氧甘露醇（1,5-二脱氧-1,5-氨基-d -甘露醇，dMM；图1）对IgM和IgD的生物合成的作用。dMM是1-脱氧诺吉里霉素（dNM；图1）的甘露糖类似物，它本身是一种葡萄糖苷酶抑制剂2 - 4。我们提出的证据表明，dMM是甘露糖苷酶抑制剂。在体内，mm抑制甘露糖酶IA/B的等效活性，并阻断高甘露糖向复合低聚糖的转化。这是首次报道的此类抑制剂。干扰n -连接聚糖的生物合成途径可能被证明是在体内操纵碳水化合物结构的有效方法。
Many secretory and membrane proteins are glycoproteins carrying asparagine-linked (N-linked) oligosaccharides. There are two types ofN-linked glycans, referred to as high-mannose and complex type, respectively. Biosynthesis ofN-linked glycans of the complex type proceeds via a high-mannose intermediate. After the initial transfer of a high-mannose oligosaccharide with the composition (Glc)3(Man)9(GlcNAc)2from a lipid carrier to the nascent polypeptide chain, trimming reactions take place. Trimming glucosidases remove the glucose residues quantitatively and mannosidases IA/B and II can remove all but three mannose residues. After trimming, terminal sugars such asN-acetylglucosamine, galactose, sialic acid and fucose may be added and result in the conversion to a glycan of the complex type1. Because suitable inhibitors were lacking, it was difficult to assess the importance of the trimming reactions for proper intracellular traffic, modification reactions other than the addition of terminal sugars, or as regulatory steps in glycoprotein processing. Here we describe the action of 1-deoxymannojirimycin (1,5-dideoxy-1,5-imino-D-mannitol, dMM; Fig. 1) on the biosynthesis of IgM and IgD. dMM is the mannose analogue of 1-deoxynojirimycin (dNM; Fig. 1), itself a glucosidase inhibitor2–4. We present evidence that dMM is a mannosidase inhibitor.In vivodMM inhibits the equivalent of the mannosidase IA/B activities and blocks conversion of high-mannose to complex oligosaccharides. It is the first such inhibitor to be reported. Interference with the biosynthetic pathway ofN-linked glycans could prove to be a powerful way to manipulate carbohydrate structurein vivo.