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首页> 外文期刊>Chemistry: A European journal >Fullerene-sp~2-Iminosugar Balls as Multimodal Ligands for Lectins and Glycosidases: A Mechanistic Hypothesis for the Inhibitory Multivalent Effect
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Fullerene-sp~2-Iminosugar Balls as Multimodal Ligands for Lectins and Glycosidases: A Mechanistic Hypothesis for the Inhibitory Multivalent Effect

机译：富勒烯-sp〜2-氨基糖球作为凝集素和糖苷酶的多峰配体：抑制多价效应的机制假说。

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Concerted functioning of lectins and carbohydrate-processing enzymes, mainly glycosidases, is essential in maintaining life. It was commonly assumed that the mechanisms by which each class of protein recognizes their cognate sugar partners are intrinsically different: multivalency is a characteristic feature of carbohydrate-lectin interactions, whereas glycosidases bind to their substrates or substrate-analogue inhibitors in monovalent form. Recent observations on the glycosidase inhibitory potential of multivalent glycomimetics have questioned this paradigm and led to postulate an inhibitory multivalent effect. Here the mechanisms at the origin of this phenomenon have been investigated. A d-gluco-configured sp~2-iminosugar glycomimetic motif, namely 1-amino-5N,6O-oxomethylydenenojirimycin (1N-ONJ), behaving, simultaneously, as a ligand of peanut agglutinin (PNA) lectin and as an inhibitor of several glycosidases, has been identified. Both the 1N-ONJ-lectin-and 1N-ONJ-glycosidase-recognition processes have been found to be sensitive to multivalency, which has been exploited in the design of a lectin-glycosidase competitive assay to explore the implication of catalytic and non-glycone sites in enzyme binding. A set of isotropic dodecavalent C_(60)-fullerene-sp~2-iminosugar balls incorporating matching or mismatching motifs towards several glycosidases (inhitopes) was synthesized for that purpose, thereby preventing differences in binding modes arising from orientational preferences. The data supports that: 1) multivalency allows modulating the affinity and selectivity of a given inhitope towards glycosidases; 2) multivalent presentation can switch on the inhibitory capacity for some inhitope-glycosidase pairs, and 3) interactions of the multivalent inhibitors with non-glycone sites is critical for glycosidase recognition. The ensemble of results point to a shift in the binding mode on going from monovalent to multivalent systems: in the first case a typical "key-lock" model involving, essentially, the high-affinity active site can be assumed, whereas in the second, a lectinlike behavior implying low-affinity non-glycone sites probably operates. The differences in responsiveness to multivalency for different glycosidases can then be rationalized in terms of the structure and accessibility of the corresponding carbohydrate-binding regions.
机译：凝集素和碳水化合物加工酶（主要是糖苷酶）的协调功能对于维持生命至关重要。通常认为每种蛋白质识别其同源糖伴侣的机制本质上是不同的：多价是碳水化合物-凝集素相互作用的特征，而糖苷酶以单价形式结合其底物或底物类似物抑制剂。关于多价糖模拟物的糖苷酶抑制潜能的最新观察已经质疑了这种范例，并导致了其抑制性多价作用。在这里，已经研究了这种现象产生的机理。 d-葡萄糖构型的sp〜2-亚氨基糖的糖基序，即1-amino-5N，6O-氧代甲基延胡索霉素（1N-ONJ），同时表现为花生凝集素（PNA）凝集素的配体和多种抑制剂糖苷酶，已被鉴定。已发现1N-ONJ-凝集素和1N-ONJ-糖苷酶的识别过程均对多价敏感，这已被用于设计凝集素-糖苷酶竞争性试验，以探索催化和非糖苷的含义。酶结合位点。为此目的，合成了一组各向同性的十二价C_（60）-富勒烯-sp_2-亚氨基糖球，其向多个糖苷酶（凤梨）掺入匹配或错配的基序，从而防止了由取向偏好引起的结合模式的差异。数据支持：1）多价允许调节给定的抗体对糖苷酶的亲和力和选择性; 2）多价呈递可以打开对某些糖苷-糖苷酶对的抑制能力，并且3）多价抑制剂与非糖苷位点的相互作用对于糖苷酶的识别至关重要。结果的整体表明从单价系统到多价系统的结合模式发生了转变：在第一种情况下，可以假设一种典型的“钥匙锁”模型，该模型本质上涉及高亲和力活性位点，而在第二种情况下，表明低亲和力非糖苷位点的凝集素样行为可能起作用。然后可以根据相应的碳水化合物结合区的结构和可及性，合理化对不同糖苷酶的多价响应性的差异。

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