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

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

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87 Scopus citations

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 Biology
Volume8
Issue number6
DOIs
StatePublished - Jun 21 2001

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    Gourley, D. G., Schüttelkopf, A. W., Leonard, G. A., Luba, J., Hardy, L. W., Beverley, S. M., & Hunter, W. N. (2001). Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites. Nature Structural Biology, 8(6), 521-525. https://doi.org/10.1038/88584