title: Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites.
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.
authors.affiliation: The Wellcome Trust Biocentre, University of Dundee, Dundee, DD1 5EH, UK.
authors.forename: D G
authors.initials: DG
authors.lastname: Gourley
authors.forename: A W
authors.initials: AW
authors.lastname: Schüttelkopf
authors.forename: G A
authors.initials: GA
authors.lastname: Leonard
authors.forename: J
authors.initials: J
authors.lastname: Luba
authors.forename: L W
authors.initials: LW
authors.lastname: Hardy
authors.forename: S M
authors.initials: SM
authors.lastname: Beverley
authors.forename: W N
authors.initials: WN
authors.lastname: Hunter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004093:Dihydropteridine Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000378:metabolism / Q000494:pharmacology; D006860:Hydrogen Bonding; D018320:Leishmania major / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008727:Methotrexate / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D017433:Protein Structure, Secondary; D011622:Pterins / Q000378:metabolism*; D012645:Selenomethionine / Q000378:metabolism; D013379:Substrate Specificity; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
chemical_list: D005493:Folic Acid Antagonists; D011622:Pterins; D009249:NADP; D012645:Selenomethionine; D013762:Tetrahydrofolate Dehydrogenase; D004093:Dihydropteridine Reductase; D008727:Methotrexate