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dc.contributor.authorGourley, David G.
dc.contributor.authorSchuttelkopf, Alexander W.
dc.contributor.authorLeonard, Gordon A.
dc.contributor.authorLuba, James
dc.contributor.authorHardy, Larry W.
dc.contributor.authorBeverley, Stephen M.
dc.contributor.authorHunter, William N.
dc.date2022-08-11T08:08:58.000
dc.date.accessioned2022-08-23T16:13:57Z
dc.date.available2022-08-23T16:13:57Z
dc.date.issued2001-05-25
dc.date.submitted2008-09-17
dc.identifier.citationNat Struct Biol. 2001 Jun;8(6):521-5. <a href="http://dx.doi.org/10.1038/88584">Link to article on publisher's site</a>
dc.identifier.issn1072-8368 (Print)
dc.identifier.doi10.1038/88584
dc.identifier.pmid11373620
dc.identifier.urihttp://hdl.handle.net/20.500.14038/33744
dc.description.abstractPteridine 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11373620&dopt=Abstract">Link to article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1038/88584
dc.subjectAmino Acid Sequence; Animals; Binding Sites; Crystallography, X-Ray; Dihydropteridine Reductase; *Drug Resistance; Folic Acid Antagonists; Hydrogen Bonding; Leishmania major; Methotrexate; Models, Molecular; Molecular Sequence Data; NADP; Oxidation-Reduction; Protein Structure, Secondary; Pterins; Selenomethionine; Substrate Specificity; Tetrahydrofolate Dehydrogenase
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titlePteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites
dc.typeJournal Article
dc.source.journaltitleNature structural biology
dc.source.volume8
dc.source.issue6
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/406
dc.identifier.contextkey632016
html.description.abstract<p>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.</p>
dc.identifier.submissionpathgsbs_sp/406
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.source.pages521-5


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