生物谷報(bào)道：幽門螺桿菌（Helicobacter pylori,，Hp）是一種螺旋狀厭氧細(xì)菌,，與慢性胃炎,、胃粘膜相關(guān)淋巴樣組織（MALT)淋巴瘤等疾病的發(fā)生都有密切關(guān)系,，也是目前唯一被確認(rèn)為胃癌致病因素之一的細(xì)菌,。脂肪酸是生物體內(nèi)一類具有十分重要生理活性和生物學(xué)功能的物質(zhì),。β-羥酯酰脫水酶（FabZ）是II型脂肪酸合成途徑脂肪酸碳鏈延長(zhǎng)循環(huán)階段中的一個(gè)重要的酶，是藥物設(shè)計(jì)的重要靶標(biāo),。
近日,，中科院上海藥物所藥理三室沈旭課題組與藥物發(fā)現(xiàn)與設(shè)計(jì)中心蔣華良課題組合作，博士生張良和劉偉治通過(guò)高通量篩選技術(shù)發(fā)現(xiàn)兩個(gè)高活性HpFabZ小分子抑制劑,，同時(shí)獲得HpFabZ和HpFabZ-抑制劑晶體并分別成功解析了其晶體結(jié)構(gòu),。首次報(bào)道的HpFabZ以及HpFabZ-抑制劑復(fù)合物晶體結(jié)構(gòu)顯示HpFabZ具有獨(dú)特的α4螺旋，它在HpFabZ的口袋結(jié)構(gòu)中起重要作用,，同時(shí)HpFabZ氨基酸Tyr100對(duì)于HpFabZ的催化可能具有非常重要的作用,；抑制劑通過(guò)兩種截然不同的結(jié)合方式抑制HpFabZ活性。這一研究成果具有重要的學(xué)術(shù)價(jià)值,，為研究HpFabZ的催化機(jī)理以及基于HpFabZ的藥物設(shè)計(jì)提供了重要的結(jié)構(gòu)信息,。相應(yīng)研究成果已發(fā)表在美國(guó)《生物化學(xué)雜志》（J. Biol. Chem. ）上。 （生物谷www.bioon.com）
生物谷推薦原始出處：
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.
