Helicobacter pylori is a major human pathogen that colonizes the gastric mucosa, leading to gastric inflammation that can progress to chronic gastritis, peptic ulcer, gastric cancer or mucosal-associated lymphoma. The ability of H. pylori to establish a chronic infection in the human stomach indicates that it is well adapted to acquire the nutrients it needs for growth in this unique environment. Complete genomic sequences for two unrelated H. pylori strains, 26695 and J99, have greatly aided the understanding of the physiology of this bacterium. Both sequenced strains were reported recently to have the genes for a potential acetone carboxylase, an enzyme that initiates the metabolism of acetone by converting it to acetoacetate. Acetone is produced in the body upon the spontaneous decarboxylation of acetoacetate, one of the ketone bodies produced by the liver and used as an energy source when glucose is not readily available. Ketones are always present in the blood, with up to 185 grams of ketone bodies produced per day by the liver of a healthy adult. This proposal will test the hypothesis that H. pylori utilizes acetone as an important energy source for the bacterium in the gastric mucosa. The first specific aim of the proposal is to verify that H. pylori has a functional acetone carboxylase by expressing the protein in Escherichia coli, purifying it, and examining its ability to catalyze the carboxylation of acetone. The second specific aim is to determine if this enzyme is needed by H. pylori to establish a chronic infection in the gastric mucosa. The operon encoding the H. pylori acetone carboxylase will be disrupted and the resulting mutant strain will be examined for its ability to colonize the stomachs of mice and Mongolian gerbils. The proposed studies will expand knowledge of metabolic pathways in H. pylori, which will lead to a better understanding of how this pathogen establishes infections in humans and may provide new strategies for the prevention or treatment of H. pylori infections. ? ?
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