TAILIEUCHUNG - Báo cáo khoa học: Characterization of the NAD(P)H oxidase and metronidazole reductase activities of the RdxA nitroreductase of Helicobacter pylori

Metronidazole (MTZ) is widely used in combination therapies against the human gastric pathogenHelicobacter pylori. Resistance to this drug is com-mon among clinical isolates and results from loss-of-function mutations in rdxA, which encodes an oxygen-insensitive nitroreductase. The RdxA-associated MTZ-reductase activity ofH. pyloriis lost upon cell disruption. Here we provide a mechanistic explanation for this phenomenon. | Characterization of the NAD P H oxidase and metronidazole reductase activities of the RdxA nitroreductase of Helicobacter pylori Igor N. Olekhnovich1 2 Avery Goodwin3 and Paul S. Hoffman1 2 1 Department of Medicine University of Virginia Schoolof Medicine Charlottesville VA USA 2 Department of Microbiology University of Virginia Schoolof Medicine Charlottesville VA USA 3 Food and Drug Administration Center for Drug Evaluation and Research Silver Spring MD USA Keywords flavoprotein Helicobacter metronidazole NAD P H oxidase nitroreductase Correspondence P. S. Hoffman Division of Infectious Diseases and InternationalHealth Room 2146 MR-4 Bldg 409 Lane Road University of Virginia Health System Charlottesville VA 22908 USA Fax 1 434 924 0075 Tel 1 434 924 2893 E-mail psh2n@ Received 8 January 2009 revised 8 April 2009 accepted 14 April 2009 doi Metronidazole MTZ is widely used in combination therapies against the human gastric pathogen Helicobacter pylori. Resistance to this drug is common among clinical isolates and results from loss-of-function mutations in rdxA which encodes an oxygen-insensitive nitroreductase. The RdxA-associated MTZ-reductase activity of H. pylori is lost upon cell disruption. Here we provide a mechanistic explanation for this phenomenon. Under aerobic conditions His6-tagged RdxA protein purified from Escherichia coli catalyzed NAD P H-dependent reductions of nitroaromatic and quinone substrates including nitrofurazone nitrofurantoin furazolidone CB1954 and 1 4-benzoquinone but not MTZ. Unlike other nitroreductases His6-RdxA exhibited potent NAD P H-oxidase activity kcat s-1 which suggested two possible explanations for the role of oxygen in MTZ reduction a NAD P H-oxidase activity promotes cellular hypoxia nonspecific reduction of MTZ and b molecular oxygen out-competes MTZ for reducing equivalents. The first hypothesis was eliminated upon finding that rdxA expression although increasing MTZ .

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