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Structural basis for catalytic and inhibitory mechanisms of beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ)

文献类型：期刊论文

作者Zhang, Liang2; Liu, Weizhi2; Hu, Tiancen2; Du, Li2; Luo, Cheng2; Chen, Kaixian2; Shen, Xu1,2; Jiang, Hualiang1,2
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
出版日期2008-02-29
卷号283期号:9页码:5370-5379
ISSN号0021-9258
DOI10.1074/jbc.M705566200
文献子类Article
英文摘要beta-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 alpha-helix (alpha 4) between alpha 3 and beta 3, 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.
WOS关键词FATTY-ACID BIOSYNTHESIS ; PLASMODIUM-FALCIPARUM ; ESCHERICHIA-COLI ; HELICOBACTER-PYLORI ; CRYSTAL-STRUCTURE ; ACP DEHYDRATASE ; DISCOVERY ; ISOMERASE ; ALIGNMENT ; TARGETS
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:000253426700017
出版者AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
源URL[http://119.78.100.183/handle/2S10ELR8/272971]  
专题药理学第三研究室
通讯作者Shen, Xu
作者单位1.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr,State Key Lab Drug Re, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Zhang, Liang,Liu, Weizhi,Hu, Tiancen,et al. Structural basis for catalytic and inhibitory mechanisms of beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ)[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2008,283(9):5370-5379.
APA Zhang, Liang.,Liu, Weizhi.,Hu, Tiancen.,Du, Li.,Luo, Cheng.,...&Jiang, Hualiang.(2008).Structural basis for catalytic and inhibitory mechanisms of beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ).JOURNAL OF BIOLOGICAL CHEMISTRY,283(9),5370-5379.
MLA Zhang, Liang,et al."Structural basis for catalytic and inhibitory mechanisms of beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ)".JOURNAL OF BIOLOGICAL CHEMISTRY 283.9(2008):5370-5379.

入库方式： OAI收割

来源：上海药物研究所

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