Mol Microbiol 2001 Nov 01;424:1021-34. doi: 10.1046/j.1365-2958.2001.02689.x.

The Helicobacter pylori UreI protein: role in adaptation to acidity and identification of residues essential for its activity and for acid activation.

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Helicobacter pylori is a human gastric pathogen that survives the strong acidity of the stomach by virtue of its urease activity. This activity produces ammonia, which neutralizes the bacterial microenvironment. UreI, an inner membrane protein, is essential for resistance to low pH and for the gastric colonization of mice by H. pylori. In the heterologous Xenopus oocytes expression system, UreI behaves like an H+-gated urea channel, and His-123 was found to be important for low pH activation. We investigated the role of UreI directly in H. pylori and showed that, in the presence of urea, strains expressing wild-type UreI displayed very rapid stimulation of extracellular ammonia production upon exposure to pH </= 5. This response was not observed when acetamide was used as a source of ammonia; therefore, it is specific for urea hydrolysis. To identify residues critical for UreI activity or activation, we constructed H. pylori strains carrying individual chromosomal mutations of UreI (i) in the four conserved histidine residues (H71, H123, H131, H193) and (ii) in a conserved region of the third intracellular loop (L165, G166, K167, F168). The distal H193 (and not H123) was found to be crucial for stimulating the production of ammonia at low pH; a single mutation in this residue uncoupled the UreI activity from its acid activation. The third intracellular loop of UreI was shown to be important for UreI activity. Thus, in H. pylori, UreI is necessary for the adaptation of urease activity to the extracellular pH. UreI behaves like a novel type of urea transporter, and the identification of residues essential for its function in H. pylori provides new insight into the unusual molecular mechanism of low pH activation.

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