Liu Jai-Shin, Cheng Wen-Chi, Wang Hung-Jung, Chen Yen-Cheng, Wang Wen-Ching
Institute of Molecular and Cellular Biology and Department of Life Sciences, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 300, Taiwan.
Biochem Biophys Res Commun. 2008 Aug 15;373(1):1-7. doi: 10.1016/j.bbrc.2008.05.070. Epub 2008 May 27.
Dehydroquinate synthase (DHQS) is a nicotinamide adenine dinucleotide (NAD)-dependent enzyme that converts 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) into 3-dehydroquinate (DHQ). Since it catalyzes the second key step in the shikimate pathway, which is crucial for the aromatic amino acid metabolism in bacteria, fungi, and plants, but not in mammals, DHQS is a potential target for new antimicrobial agents, anti-parasitic agents and herbicides. The crystal structure of Helicobacter pylori DHQS (HpDHQS) complexed with NAD has been determined at 2.4-A resolution and was found to possess an N-terminal Rossmann-fold domain and a C-terminal alpha-helical domain. Structural comparison reveals that the binary complex adopts an open-state conformation and shares conserved residues in the binding pocket. Virtual docking of compounds into the active site of the HpDHQS structure using the GOLD docking program led to the identification of several inhibitors. The most active compound had an IC(50) value of 61 microM, which may serve as a lead for potent inhibitors.
脱氢奎尼酸合酶（DHQS）是一种依赖烟酰胺腺嘌呤二核苷酸（NAD）的酶，它将7-磷酸-3-脱氧-D-阿拉伯庚酮糖（DAHP）转化为3-脱氢奎尼酸（DHQ）。由于它催化莽草酸途径中的第二个关键步骤，该途径对细菌、真菌和植物中的芳香族氨基酸代谢至关重要，但对哺乳动物则不然，因此DHQS是新型抗菌剂、抗寄生虫剂和除草剂的潜在靶点。已确定与NAD复合的幽门螺杆菌DHQS（HpDHQS）的晶体结构，分辨率为2.4埃，发现其具有一个N端罗斯曼折叠结构域和一个C端α-螺旋结构域。结构比较表明，二元复合物采用开放状态构象，并且在结合口袋中具有保守残基。使用GOLD对接程序将化合物虚拟对接至HpDHQS结构的活性位点，从而鉴定出几种抑制剂。活性最高的化合物的IC（50）值为61微摩尔，可作为强效抑制剂的先导化合物。
