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GMP synthase is essential for viability and infectivity of Trypanosoma bruceidespite a redundant purine salvage pathway

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dc.contributor.authorLi, Qiong
dc.contributor.authorLeija, Christopher
dc.contributor.authorRijo-Ferreira, Filipa
dc.contributor.authorChen, Jun
dc.contributor.authorCestari, Igor
dc.contributor.authorStuart, Kenneth
dc.contributor.authorTu, Benjamin P.
dc.contributor.authorPhillips, Margaret A.
dc.date.accessioned2022-04-20T16:23:25Z
dc.date.available2022-04-20T16:23:25Z
dc.date.issued2015
dc.description© 2015 John Wiley & Sons Ltd.pt_PT
dc.description.abstractThe causative agent of human African trypanosomiasis, Trypanosoma brucei, lacks de novo purine biosynthesis and depends on purine salvage from the host. The purine salvage pathway is redundant and contains two routes to guanosine-5'-monophosphate (GMP) formation: conversion from xanthosine-5'-monophosphate (XMP) by GMP synthase (GMPS) or direct salvage of guanine by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). We show recombinant T. brucei GMPS efficiently catalyzes GMP formation. Genetic knockout of GMPS in bloodstream parasites led to depletion of guanine nucleotide pools and was lethal. Growth of gmps null cells was only rescued by supraphysiological guanine concentrations (100 μM) or by expression of an extrachromosomal copy of GMPS. Hypoxanthine was a competitive inhibitor of guanine rescue, consistent with a common uptake/metabolic conversion mechanism. In mice, gmps null parasites were unable to establish an infection demonstrating that GMPS is essential for virulence and that plasma guanine is insufficient to support parasite purine requirements. These data validate GMPS as a potential therapeutic target for treatment of human African trypanosomiasis. The ability to strategically inhibit key metabolic enzymes in the purine pathway unexpectedly bypasses its functional redundancy by exploiting both the nature of pathway flux and the limited nutrient environment of the parasite's extracellular niche.pt_PT
dc.description.sponsorshipThis work was supported by National Institutes of Health grants 1R01AI078962 (to KS and MAP), 2R37AI034432 (to MAP) and GM007062 (to CL); the Welch Foundation grant I-1257 (to MAP) and Fundação para a Ciência e Tecnologia (FCT, Portugal) SFRH/BD/51286/2010 to FRF.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMol Microbiol. 2015 Sep;97(5):1006-1020pt_PT
dc.identifier.doi10.1111/mmi.13083pt_PT
dc.identifier.eissn1365-2958
dc.identifier.issn0950-382X
dc.identifier.urihttp://hdl.handle.net/10451/52464
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationPROGRAMA GRADUADO EM BIOLOGIA BÁSICA E APLICADA DA UNIVERSIDADE DO PORTO
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/journal/13652958pt_PT
dc.titleGMP synthase is essential for viability and infectivity of Trypanosoma bruceidespite a redundant purine salvage pathwaypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberSFRH/BD/51286/2010
oaire.awardTitlePROGRAMA GRADUADO EM BIOLOGIA BÁSICA E APLICADA DA UNIVERSIDADE DO PORTO
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F51286%2F2010/PT
oaire.citation.endPage1020pt_PT
oaire.citation.issue5pt_PT
oaire.citation.startPage1006pt_PT
oaire.citation.titleMolecular Microbiologypt_PT
oaire.citation.volume97pt_PT
oaire.fundingStreamOE
person.familyNameRijo-Ferreira
person.givenNameFilipa
person.identifier750870
person.identifier.ciencia-id7E1A-ED0E-636C
person.identifier.orcid0000-0002-4003-020X
person.identifier.scopus-author-id56261883100
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication56fd4f5e-09a9-4739-bf21-6165f21cf944
relation.isAuthorOfPublication.latestForDiscovery56fd4f5e-09a9-4739-bf21-6165f21cf944
relation.isProjectOfPublication2e53e211-9864-45a1-aac9-aa96b42b69e6
relation.isProjectOfPublication.latestForDiscovery2e53e211-9864-45a1-aac9-aa96b42b69e6

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