• Login
    JavaScript is disabled for your browser. Some features of this site may not work without it.
    An essential type I nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs 
    •   QMRO Home
    • School of Biological and Chemical Sciences
    • School of Biological and Chemical Sciences
    • An essential type I nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs
    •   QMRO Home
    • School of Biological and Chemical Sciences
    • School of Biological and Chemical Sciences
    • An essential type I nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs
    ‌
    ‌

    Browse

    All of QMROCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects
    ‌
    ‌

    Administrators only

    Login
    ‌
    ‌

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    An essential type I nitroreductase from Leishmania major can be used to activate leishmanicidal prodrugs

    View/Open
    Accepted version (296.6Kb)
    Volume
    288
    Pagination
    28466 - 28476 (11)
    Publisher URL
    http://www.jbc.org/content/early/2013/08/14/jbc.M113.494781.full.pdf+html
    DOI
    10.1074/jbc.M113.494781
    Journal
    Journal of Biological Chemistry
    Issue
    40
    Metadata
    Show full item record
    Abstract
    Nitroaromatic prodrugs are used to treat a range of microbial infections with selectivity achieved by specific activation reactions. For trypanosomatid parasites this is mediated by type I nitroreductases (NTRs). Here, we demonstrate that the causative agent of leishmaniasis, Leishmania major, expresses a FMN-containing NTR (LmNTR) that metabolises a wide range of substrates and based on electron donor and acceptor preferences may function as a NADH:quinone oxidoreductase. Using gene deletion approaches, we demonstrate that this activity is essential to L. major promastigotes, the parasite forms found in the insect vector. Intriguingly, although LmNTR+/- heterozygote promastigote parasites could differentiate into infectious form metacyclic cells, these were unable to establish infections in cultured mammalian cells and cause delayed pathology in mice. Further, we exploit the LmNTR activity evaluating a library of nitrobenzylphosphoramide mustards using biochemical and phenotypic screens. We identify a subset of compounds that display significant growth inhibitory properties against the intracellular parasite form found in the mammalian host. The leishmanicidal activity was shown to be LmNTR specific as the LmNTR+/- heterozygote promastigotes displayed resistance to the most potent mustards. We conclude that LmNTR can be targeted for drug development by exploiting its prodrug activating property or by designing specific inhibitors to block its endogenous function
    Authors
    Voak, AA; Gobalakrishnapillai, V; Seifert, K; Balczo, E; Hu, L; Hall, BS; WILKINSON, SR
    URI
    http://qmro.qmul.ac.uk/xmlui/handle/123456789/12388
    Collections
    • School of Biological and Chemical Sciences [1659]
    Licence information
    “The final publication is available at http://www.jbc.org/content/288/40/28466.short”
    Copyright statements
    Copyright © 2013, The American Society for Biochemistry and Molecular Biology
    Twitter iconFollow QMUL on Twitter
    Twitter iconFollow QM Research
    Online on twitter
    Facebook iconLike us on Facebook
    • Site Map
    • Privacy and cookies
    • Disclaimer
    • Accessibility
    • Contacts
    • Intranet
    • Current students

    Modern Slavery Statement

    Queen Mary University of London
    Mile End Road
    London E1 4NS
    Tel: +44 (0)20 7882 5555

    © Queen Mary University of London.