van Rijssel Erwin R, Janssen Antonius P A, Males Alexandra, Davies Gideon J, van der Marel Gijsbert A, Overkleeft Herman S, Codée Jeroen D C
Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
York Structural Biology Laboratory, Department of Chemistry, The University of York, York, YO10 5DD, UK.
Chembiochem. 2017 Jul 4;18(13):1297-1304. doi: 10.1002/cbic.201700080. Epub 2017 Apr 18.
A set of mannuronic-acid-based iminosugars, consisting of the C-5-carboxylic acid, methyl ester and amide analogues of 1deoxymannorjirimicin (DMJ), was synthesised and their pH-dependent conformational behaviour was studied. Under acidic conditions the methyl ester and the carboxylic acid adopted an "inverted" C chair conformation as opposed to the "normal" C chair at basic pH. This conformational change is explained in terms of the stereoelectronic effects of the ring substituents and it parallels the behaviour of the mannuronic acid ester oxocarbenium ion. Because of this solution-phase behaviour, the mannuronic acid ester azasugar was examined as an inhibitor for a Caulobacter GH47 mannosidase that hydrolyses its substrates by way of a reaction itinerary that proceeds through a H transition state. No binding was observed for the mannuronic acid ester azasugar, but sub-atomic resolution data were obtained for the DMJ⋅CkGH47 complex, showing two conformations- S and C -for the DMJ inhibitor.
合成了一组基于甘露糖醛酸的亚氨基糖，包括1-脱氧甘露基梨醇糖苷（DMJ）的C-5-羧酸、甲酯和酰胺类似物，并研究了它们随pH变化的构象行为。在酸性条件下，甲酯和羧酸采取“反式”C椅式构象，而在碱性pH下为“正常”C椅式构象。这种构象变化用环取代基的立体电子效应来解释，并且与甘露糖醛酸酯氧碳鎓离子的行为相似。由于这种溶液相行为，研究了甘露糖醛酸酯氮杂糖作为新月柄杆菌GH47甘露糖苷酶抑制剂的情况，该酶通过一个经过H过渡态的反应历程水解其底物。未观察到甘露糖醛酸酯氮杂糖的结合，但获得了DMJ·CkGH47复合物的亚原子分辨率数据，显示DMJ抑制剂有两种构象——S型和C型。
