2glp: Difference between revisions

ss-hydroxyacyl-ACP dehydratase (FabZ) is an important enzyme for the elongation cycles of 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 a-helix (a4), which plays an important role in shaping the substrate-binding tunnel. Residue Tyr100 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 Tyr100 in catalytic activity and substrate binding. Residue Phe83 at the exit tunnel was also refined in two alternative conformations, leading the tunnel to form L-shape and U-shape. All these data thus contributed a lot 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 is expected to have provided some insights into the catalytic and inhibitory mechanisms of FabZ thus facilitating the antibacterial agent development.

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