Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites

David G. Gourley, Alexander W. Schuttelkopf, Gordon A. Leonard, James Luba, Larry W. Hardy, Stephen M. Beverley, William N. Hunter

    Research output: Contribution to journalArticle

    87 Citations (Scopus)

    Abstract

    Pteridine reductase (PTR1) is a short-chain reductase (SDR) responsible for the salvage of pterins in parasitic trypanosomatids. PTR1 catalyzes the NADPH-dependent two-step reduction of oxidized pterins to the active tetrahydro-forms and reduces susceptibility to antifolates by alleviating dihydrofolate reductase (DHFR) inhibition. Crystal structures of PTR1 complexed with cofactor and 7,8-dihydrobiopterin (DHB) or methotrexate (MTX) delineate the enzyme mechanism, broad spectrum of activity and inhibition by substrate or an antifolate. PTR1 applies two distinct reductive mechanisms to substrates bound in one orientation. The first reduction uses the generic SDR mechanism, whereas the second shares similarities with the mechanism proposed for DHFR. Both DHB and MTX form extensive hydrogen bonding networks with NADP(H) but differ in the orientation of the pteridine
    Original languageEnglish
    Pages (from-to)521-525
    Number of pages5
    JournalNature Structural & Molecular Biology
    Volume8
    Issue number6
    DOIs
    Publication statusPublished - Jun 2001

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