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dc.contributor.authorHall, BS
dc.contributor.authorBot, C
dc.contributor.authorWilkinson, SR
dc.date.accessioned2011-05-04T11:06:50Z
dc.date.issued2011-02-23
dc.date.issued2011-02-23
dc.date.issued2011-04-15
dc.date.issued2011-04-15
dc.identifier.citationHall, B., Bot, C. and Wilkinson, S. (2011). Nifurtimox Activation by Trypanosomal Type I Nitroreductases Generates Cytotoxic Nitrile Metabolites. [online] The Journal of Biological Chemistry. Available at: http://www.jbc.org/content/286/15/13088 [Accessed 10 Nov. 2017].
dc.identifier.issn0021-9258
dc.identifier.urihttp://qmro.qmul.ac.uk/jspui/handle/123456789/982
dc.description.abstractThe prodrug nifurtimox has been used for more than 40 years to treat Chagas disease and forms part of a recently approved combinational therapy that targets West African trypanosomiasis. Despite this, its mode of action is poorly understood. Detection of reactive oxygen and nitrogen intermediates in nifurtimox-treated extracts led to the proposal that this drug induces oxidative stress in the target cell. Here, we outline an alternative mechanism involving reductive activation by a eukaryotic type I nitroreductase. Several enzymes proposed to metabolize nifurtimox, including prostaglandin F2α synthase and cytochrome P450 reductase, were overexpressed in bloodstream-form Trypanosoma brucei. Only cells with elevated levels of the nitroreductase displayed altered susceptibility to this nitrofuran, implying a key role in drug action. Reduction of nifurtimox by this enzyme was shown to be insensitive to oxygen and yields a product characterized by LC/MS as an unsaturated open-chain nitrile. This metabolite was shown to inhibit both parasite and mammalian cell growth at equivalent concentrations, in marked contrast to the parental prodrug. These experiments indicate that the basis for the selectivity of nifurtimox against T. brucei lies in the expression of a parasite-encoded type I nitroreductase.
dc.format.extent13088 - 13095
dc.relation.ispartofJ BIOL CHEM
dc.rightsAuthor's Choice—Final version full access. Creative Commons Attribution Non-Commercial License applies to Author Choice Articles
dc.subjectESCHERICHIA-COLI
dc.subjectTRYPANOTHIONE REDUCTASE
dc.subjectNITROHETEROCYCLIC DRUGS
dc.subjectNITROAROMATIC COMPOUNDS
dc.subjectCATALYTIC PROPERTIES
dc.subjectCHAGAS-DISEASE
dc.subjectFREE-RADICALS
dc.subjectCRUZI
dc.subjectRESISTANCE
dc.subjectBENZNIDAZOLE
dc.titleNifurtimox Activation by Trypanosomal Type I Nitroreductases Generates Cytotoxic Nitrile Metabolites
dc.typeJournal Article
dc.rights.holder© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
dc.identifier.doi10.1074/jbc.M111.230847
dc.relation.isPartOfJ BIOL CHEM
pubs.issue15
pubs.organisational-group/Queen Mary University of London
pubs.organisational-group/Queen Mary University of London/Faculty of Science & Engineering
pubs.organisational-group/Queen Mary University of London/Faculty of Science & Engineering/Biological and Chemical Sciences - Staff
pubs.volume286


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