Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada K1A 0R6.
Carbohydr Res. 2013 Aug 30;378:45-55. doi: 10.1016/j.carres.2012.12.017. Epub 2013 Jan 10.
In order to evaluate the importance of molecular shape of inhibitor molecules and the charge/H-bond and hydrophobic interactions, we synthesized three types of molecules and tested them against a sialyltransferase. The first type of compounds were designed as substrate mimics in which the phosphate in CMP-Neu5NAc was replaced by a non-hydrolysable, uncharged 1,2,3-triazole moiety. The second type of compound contained a 2-deoxy-2,3-dehydro-acetylneuraminic moiety which was linked to cytidine through its carboxylic acid and amide linkers. In the third type of compound the sialyl phosphate was substituted by an aryl sulfonamide which was then linked to cytidine. Inhibition study of these cytidine conjugates against Campylobacter jejuni sialyltransferase Cst 06 showed that the first type of molecules are competitive inhibitors, whereas the other two could only inhibit the enzyme non-competitively. The results indicate that although the binding specificity may be guided by molecular shape and H-bond interaction, the charge and hydrophobic interactions contributed most to the binding affinity.
为了评估抑制剂分子的分子形状以及电荷/H-键合和疏水性相互作用的重要性，我们合成了三种类型的分子并对其进行了唾液酸转移酶的测试。第一类化合物被设计为底物类似物，其中 CMP-Neu5NAc 的磷酸基团被不可水解的非电荷 1,2,3-三唑取代。第二类化合物含有 2-脱氧-2,3-脱水乙酰神经氨酸部分，该部分通过其羧酸和酰胺键与胞嘧啶连接。在第三类化合物中，唾液酸磷酸被芳基磺酰胺取代，然后与胞嘧啶连接。这些胞嘧啶缀合物对空肠弯曲杆菌唾液酸转移酶 Cst 06 的抑制研究表明，第一类分子是竞争性抑制剂，而其他两种只能非竞争性地抑制酶。结果表明，尽管结合特异性可能受到分子形状和氢键相互作用的指导，但电荷和疏水性相互作用对结合亲和力的贡献最大。
