Structure-Based Inhibitors Exhibit Differential Activities against Helicobacter pylori and Escherichia coli Undecaprenyl Pyrophosphate Synthases

Figure 1

Crystal structures of H. pylori UPPS. (a) Two subunits of the apoenzyme are superimposed. The most obvious disposition occurs in α3 helix which adopts an open form and a closed form in subunit A and B, respectively. At the top of the tunnel-shaped crevice surrounded by 2α-helices and 4β-strands is the substrate-binding site. Phe124 located at the bottom of the H. pylori UPPS tunnel adopts a similar position to that of Leu137 in E. coli UPPS, essential for determining product chain length. (b) Superimposition of active site structures of H. pylori UPPS with FsPP and E. coli UPPS with FsPP, Mg²⁺, and IPP [9]. The active site residues in H. pylori UPPS are shown in pink and those in E. coli UPPS in white for carbon-carbon bonds in ball-and-stick model. The thiopyrophosphate (visible in crystal structure) is shown in black, the nitrogen atoms and Mg²⁺ ion are shown in blue, and oxygen atoms are shown in red. Asp13 in H. pylori UPPS occupies a similar position to that of Asp26 in E. coli UPPS to coordinate with an Mg²⁺ for binding with the pyrophosphate leaving group of FPP.

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