Temple University School of Pharmacy, Department of Pharmaceutical Sciences, 3307 North Broad Street, Philadelphia, PA 19140, USA.
Bioorg Med Chem Lett. 2011 May 1;21(9):2764-8. doi: 10.1016/j.bmcl.2010.10.045. Epub 2010 Oct 14.
The 2,4,6-trimethylpyridinium derivative of histamine is an effective activator of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). However, unlike other CA activators, which bind at the entrance of the active site cavity, an X-ray crystal structure of hCA II in complex with the 1-[2-(1H-imidazol-4-yl)-ethyl]-2,4,6-trimethylpyridinium salt evidenced a binding mode never observed before either for activators or inhibitors of this enzyme, with the 2,4,6-trimethylpyridinium ring pointing towards the metal ion deep within the enzyme cavity, and several strong hydrophobic interactions stabilizing the adduct. Indeed, incubation of the activator with the enzyme for several days leads to potent inhibitory effects. This is the first example of a CA activator which after a longer contact with the enzyme behaves as an inhibitor.
组胺的 2,4,6-三甲基吡啶鎓衍生物是锌酶碳酸酐酶（CA，EC 4.2.1.1）的有效激活剂。然而，与其他 CA 激活剂不同，它们结合在活性位点腔的入口处，与 hCA II 复合物的 X 射线晶体结构表明，与该酶的激活剂或抑制剂从未观察到的结合模式，2,4,6-三甲基吡啶鎓环指向金属离子在酶腔深处，并且几个强疏水性相互作用稳定加合物。事实上，将激活剂与酶孵育数天会导致强烈的抑制作用。这是第一个与酶接触较长时间后表现出抑制剂特性的 CA 激活剂的例子。
