We are upgrading the repository! A content freeze is in effect until December 6, 2024. New submissions or changes to existing items will not be allowed during this period. All content already published will remain publicly available for searching and downloading. Updates will be posted in the Website Upgrade 2024 FAQ in the sidebar Help menu. Reach out to escholarship@umassmed.edu with any questions.

Show simple item record

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

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.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.departmentMorningside Graduate School of Biomedical Sciences
dc.source.pages521-5


This item appears in the following Collection(s)

Show simple item record