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

Nature Structural Biology volume 8, pages 521–525 (2001)Cite this article

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.

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Figure 1: The sequence and structure of L. major PTR1.
Figure 2: The interactions of DHB with PTR1 and NADP+.
Figure 3: The mechanism of PTR1.
Figure 4: The interactions of MTX with PTR1 and NADPH.

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Acknowledgements

We thank C. Bond, C. Frieden, D. Hall and A. Mehlert for discussions, and Daresbury and ESRF for support. Funded by the Wellcome Trust, BBSRC and N.I.H. grants.

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Author notes

  1. David G. Gourley, Alexander W. Schüttelkopf and Stephen M. Beverley: The first two authors contributed equally to this research.

Authors and Affiliations

  1. The Wellcome Trust Biocentre, University of Dundee, Dundee, DD1 5EH, UK

    David G. Gourley, Alexander W. Schüttelkopf & William N. Hunter

  2. Joint Structural Biology Group, ESRF, BP 220, Grenoble, F38043, Cedex 9, France

    Gordon A. Leonard

  3. Department of Pharmacology Molecular Toxicology, University of Massachusetts Medical School, 373 Plantation St., Worcester, 01605, Massachusetts, USA

    James Luba & Larry W. Hardy

  4. ArQule Inc., 19 Presidential Way, Woburn, 02154, Massachusetts, USA

    Larry W. Hardy

  5. Department of Molecular Microbiology, Washington University School of Medicine, Campus Box 8230, 660 S. Euclid Avenue, St. Louis, 63110-1093, Missouri, USA

    Stephen M. Beverley

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  1. David G. Gourley
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Correspondence to William N. Hunter.

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Gourley, D., Schüttelkopf, A., Leonard, G. et al. Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites. Nat Struct Mol Biol 8, 521–525 (2001). https://doi.org/10.1038/88584

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