生物谷报道：幽门螺杆菌（Helicobacter pylori，Hp）是一种螺旋状厌氧细菌，与慢性胃炎、胃粘膜相关淋巴样组织（MALT)淋巴瘤等疾病的发生都有密切关系，也是目前唯一被确认为胃癌致病因素之一的细菌。脂肪酸是生物体内一类具有十分重要生理活性和生物学功能的物质。β-羟酯酰脱水酶（FabZ）是II型脂肪酸合成途径脂肪酸碳链延长循环阶段中的一个重要的酶，是药物设计的重要靶标。
近日，中科院上海药物所药理三室沈旭课题组与药物发现与设计中心蒋华良课题组合作，博士生张良和刘伟治通过高通量筛选技术发现两个高活性HpFabZ小分子抑制剂，同时获得HpFabZ和HpFabZ-抑制剂晶体并分别成功解析了其晶体结构。首次报道的HpFabZ以及HpFabZ-抑制剂复合物晶体结构显示HpFabZ具有独特的α4螺旋，它在HpFabZ的口袋结构中起重要作用，同时HpFabZ氨基酸Tyr100对于HpFabZ的催化可能具有非常重要的作用；抑制剂通过两种截然不同的结合方式抑制HpFabZ活性。这一研究成果具有重要的学术价值，为研究HpFabZ的催化机理以及基于HpFabZ的药物设计提供了重要的结构信息。相应研究成果已发表在美国《生物化学杂志》（J. Biol. Chem. ）上。 （生物谷www.bioon.com）
生物谷推荐原始出处：
Journal of Biological Chemistry，Vol. 283, Issue 9, 5370-5379, February 29, 2008，Liang Zhang, Xu Shen, and Hualiang Jiang
Structural Basis for Catalytic and Inhibitory Mechanisms of β-Hydroxyacyl-acyl Carrier Protein Dehydratase (FabZ)*
Liang Zhang1, Weizhi Liu1, Tiancen Hu, Li Du, Cheng Luo, Kaixian Chen, Xu Shen2, and Hualiang Jiang3
From the Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China and the School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
β-Hydroxyacyl-acyl carrier protein dehydratase (FabZ) is an important enzyme for the elongation cycles of both saturated and unsaturated fatty acids biosyntheses in the type II fatty acid biosynthesis system (FAS II) pathway. FabZ has been an essential target for the discovery of compounds effective against pathogenic microbes. In this work, to characterize the catalytic and inhibitory mechanisms of FabZ, the crystal structures of the FabZ of Helicobacter pylori (HpFabZ) and its complexes with two newly discovered inhibitors have been solved. Different from the structures of other bacterial FabZs, HpFabZ contains an extra short two-turn -helix (4) between 3 and β3, which plays an important role in shaping the substrate-binding tunnel. Residue Tyr-100 at the entrance of the tunnel adopts either an open or closed conformation in the crystal structure. The crystal structural characterization, the binding affinity determination, and the enzymatic activity assay of the HpFabZ mutant (Y100A) confirm the importance of Tyr-100 in catalytic activity and substrate binding. Residue Phe-83 at the exit tunnel was also refined in two alternative conformations, leading the tunnel to form an L-shape and U-shape. All these data thus contributed much to understanding the catalytic mechanism of HpFabZ. In addition, the co-crystal structures of HpFabZ with its inhibitors have suggested that the enzymatic activity of HpFabZ could be inhibited either by occupying the entrance of the tunnel or plugging the tunnel to prevent the substrate from accessing the active site. Our study has provided some insights into the catalytic and inhibitory mechanisms of FabZ, thus facilitating antibacterial agent development.
