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dc.contributor.authorNare, Bakela
dc.contributor.authorLuba, James
dc.contributor.authorHardy, Larry W.
dc.contributor.authorBeverley, Stephen M.
dc.date2022-08-11T08:09:02.000
dc.date.accessioned2022-08-23T16:16:04Z
dc.date.available2022-08-23T16:16:04Z
dc.date.issued1997-01-01
dc.date.submitted2008-11-24
dc.identifier.citationParasitology. 1997;114 Suppl:S101-10.
dc.identifier.issn0031-1820 (Print)
dc.identifier.pmid9309772
dc.identifier.urihttp://hdl.handle.net/20.500.14038/34242
dc.description.abstractLeishmania and other trypanosomatid protozoa require reduced pteridines (pterins and folates) for growth, suggesting that inhibition of these pathways could be targeted for effective chemotherapy. This goal has not yet been realized, indicating that pteridine metabolism may be unusual in this lower eukaryote. We have investigated this possibility using both wild type and laboratory-selected antifolate-resistant strains, and with defined genetic knockouts of several pteridine metabolic genes. In Leishmania, resistance to the antifolate methotrexate is mediated through several mechanisms singly or in combination, including alterations in transport leading to reduced drug influx, overproduction (R-region amplification) or point mutation of dihydrofolate reductase-thymidylate synthase (DHFR-TS), and amplification of a novel pteridine reductase (PTR1, encoded by the H-region). All of the proteins involved are potential targets for antifolate chemotherapy. Notably, parasites in which the gene encoding dihydrofolate reductase (DHFR) has been deleted (dhfr-ts- knockouts) do not survive in animal models, validating this enzyme as a target for effective chemotherapy. However, the properties of pteridine reductase 1 (PTR1) suggest a reason why antifolate chemotherapy has so far not been successful in trypanosomatids. PTR1, by its ability to provide reduced pterins and folates, has the potential to act as a by-pass and/or modulator of DHFR inhibition under physiological conditions. Moreover, PTR1 is less sensitive to many antifolates targeted primarily against DHFR. These findings suggest that successful antifolate chemotherapy in Leishmania will have to target simultaneously both DHFR and PTR1.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9309772&dopt=Abstract">Link to article in PubMed</a>
dc.relation.urlhttp://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=23775&fulltextType=RA&fileId=S0031182097001133
dc.subjectAnimals; Drug Resistance; Folic Acid Antagonists; Leishmania; Leishmaniasis; Methotrexate; Oxidoreductases; Pteridines
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleNew approaches to Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target and modulator of antifolate sensitivity
dc.typeJournal Article
dc.source.journaltitleParasitology
dc.source.volume114 Suppl
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/898
dc.identifier.contextkey671824
html.description.abstract<p>Leishmania and other trypanosomatid protozoa require reduced pteridines (pterins and folates) for growth, suggesting that inhibition of these pathways could be targeted for effective chemotherapy. This goal has not yet been realized, indicating that pteridine metabolism may be unusual in this lower eukaryote. We have investigated this possibility using both wild type and laboratory-selected antifolate-resistant strains, and with defined genetic knockouts of several pteridine metabolic genes. In Leishmania, resistance to the antifolate methotrexate is mediated through several mechanisms singly or in combination, including alterations in transport leading to reduced drug influx, overproduction (R-region amplification) or point mutation of dihydrofolate reductase-thymidylate synthase (DHFR-TS), and amplification of a novel pteridine reductase (PTR1, encoded by the H-region). All of the proteins involved are potential targets for antifolate chemotherapy. Notably, parasites in which the gene encoding dihydrofolate reductase (DHFR) has been deleted (dhfr-ts- knockouts) do not survive in animal models, validating this enzyme as a target for effective chemotherapy. However, the properties of pteridine reductase 1 (PTR1) suggest a reason why antifolate chemotherapy has so far not been successful in trypanosomatids. PTR1, by its ability to provide reduced pterins and folates, has the potential to act as a by-pass and/or modulator of DHFR inhibition under physiological conditions. Moreover, PTR1 is less sensitive to many antifolates targeted primarily against DHFR. These findings suggest that successful antifolate chemotherapy in Leishmania will have to target simultaneously both DHFR and PTR1.</p>
dc.identifier.submissionpathgsbs_sp/898
dc.contributor.departmentDepartment of Pharmacology and Molecular Toxicology
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.source.pagesS101-10


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