拓效应和结合模式与多价值的以iminosugar为基础的葡萄糖集群和mannosidases一起运行
Yoan Brissonnet1, Carmen Ortiz Mellet, Sandrine Morandat
1LUNAM Université , CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
Journal of the American Chemical Society
|November 15, 2013
概括
多价性伊米诺糖表现出增强的葡萄糖酶抑制和选择性. 这项研究揭示了空间布局是关键的,其中一种四价化合物可以提高抗杰克豆α-曼诺酶 (JBαMan) 的功效800倍.
科学领域:
- 碳水化合物的化学成分
- 酶学 是一种酶学.
- 葡萄糖生物学 葡萄糖生物学
背景情况:
- 多价值的伊米诺糖正在研究糖酶抑制,提供潜在的亲和力增强.
- 通过多价值实现酶选择性是有吸引力的,但需要了解结合模式.
研究的目的:
- 开发具有定义拓的四值和八值免疫糖探针.
- 评估对特定的葡萄糖酶的结合亲和力,包括杰克豆α-曼诺酶 (JBαMan) 和Drosophila melanogasterII类α-曼诺酶 (GM和LM).
- 研究空间分布对抑制活性和选择性的影响.
主要方法:
- 合成多价值的伊米诺糖探针 (四价值和八价值).
- 对JBαMan,戈尔吉α-曼诺酶 (GM) 和溶酶体α-曼诺酶 (LM) 的酶抑制试验.
- 动态光散射 (DLS) 和原子力显微镜 (AFM) 用于研究结合模式.
主要成果:
- 抑制性概况根据iminosugars的空间分布而有显著的变化,即使具有相同的价值.
- 最好的四价化合物与单价参考化合物相比,对JBαMan的抑制功效增加了800倍.
- 这种化合物还增强了基因转基因对LM的抑制活性和选择性.
- DLS和AFM发现,多价值化合物通过分子间交叉链接诱导JBαMan聚合.
结论:
- 多价值胺糖的空间布局对于微调酶抑制活性和选择性至关重要.
- 多价性为开发治疗性戈尔吉α-曼诺酶 (GM) 抑制剂提供了一种可行的策略,而不会影响溶解体α-曼诺酶 (LM).
- 观察到的JBαMan聚合表明了一种涉及分子间交叉链接的机制,该机制是由酶的二维性质促进的.
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