NEW SYNTHETIC CLUSTER LIGANDS FOR GALACTOSE/N-ACETYLGALACTOSAMINE-SPECIFIC LECTIN OF MAMMALIAN LIVER
NEW SYNTHETIC CLUSTER LIGANDS FOR GALACTOSE/N-ACETYLGALACTOSAMINE-SPECIFIC LECTIN OF MAMMALIAN LIVER
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DOI：
10.1021/bi00313a037
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发表时间：
1984-01-01
期刊：
影响因子：
2.9
通讯作者：
LEE, YC
中科院分区：
文献类型：
--
作者：
LEE, RT;LIN, P;LEE, YC
制备了含有至多6个非还原性末端半乳糖残基的合成配体。该合成涉及N-苄氧基羰基天冬氨酸或N-苄氧基羰基酪氨酰-γ-的羧基的偶联。谷氨酰谷氨酸与ω-含有至多3个乳糖基残基的糖苷的糖苷配基的氨基。通过氢解除去苄氧羰基，然后将这些配体作为125 I-去唾液酸类粘蛋白与半乳糖/N-乙酰半乳糖胺凝集素结合的抑制剂进行测试，所述半乳糖/N-乙酰半乳糖胺凝集素是可溶的和在新鲜分离的哺乳动物肝细胞的表面上的。每增加一个半乳糖残基到现有的。在现有的配体结构上每增加一个半乳糖残基，都会增加这种配体的结合亲和力。然而，在每个半乳糖价态水平下，结合常数根据配体的结构变化高达1000倍。在给定的化合价水平下，簇配体的结合强度主要取决于两个因素：半乳糖间的最大空间距离和连接半乳糖残基和分支点的臂的灵活性。假定凝集素的3个半乳糖结合位点在空间上排列在边为15、22和25埃的三角形的顶点上。半乳糖间距离短于这些长度的配体在其各自的化合价水平下总是较差的配体。在具有足够长的半乳糖间距离的配体中，具有最灵活结构的配体是最好的抑制剂。用3 × 104的125 I-脱唾液酸乳清类粘蛋白抑制剂达到50%。10-7和5倍。10-8 M，分别是最好的合成二价和三价配体，这些配体的抑制能力是最具抑制性的二和三触角寡糖结构的天然来源。
Synthetic ligands containing up to 6 residues of nonreducing terminal galactose were prepared. The synthesis involved coupling of carboxyl groups of N-benzyloxycarbonylaspartic acid or of N-benzyloxycarbonyltyrosyl-.gamma.-glutamylglutamic acid to the .omega.-amino group of the aglycon of a glycoside that contained up to 3 lactosyl residues. The benzyloxycarbonyl group was removed by hydrogenolysis before these ligands were tested as inhibitors to the binding of 125I-asialoorosomucoid to the galactose/N-acetylgalactosamine lectin, both soluble and on the surface of freshly isolated mammalian hepatocytes. Each addition of a galactosyl residue to an existing. Each addition of a galactosyl residue to an existing ligand structure invariably increased the binding affinity of such a ligand. However, at each level of galactose valency, the binding constant varied as much as 1000-fold depending on the structure of the ligand. At a given level of valency, the binding strength of a cluster ligand depended mainly on 2 factors: the maximum spatial inter-galactose distances and the flexibility of the arm connecting galactosyl residues and the branch points. In has been postulated that the 3 galactose-combining sites of the lectin are arranged in space at the vertexes of a triangle whose sides are 15, 22 and 25 .ANG.. Ligands having inter-galactose distances shorter than these lengths were invariably poor ligands at their respective level of valency. Among the ligands having sufficiently long inter-galactose distances, those with the most flexible structure were the best inhibitors. The 50% inhibition of 125I-asialoorosomucoid binding was achieved by 3 .times. 10-7 and 5 .times. 10-8 M, respectively, of the best synthetic bi- and trivalent ligands, and inhibitory power of these ligands was comparable to that of the most inhibitory bi- and triantennary oligosaccharide structures of natural origin.