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dc.contributorUniversitat Ramon Llull. IQS
dc.contributor.authorPlanas, Antoni (Planas Sauter)
dc.contributor.authorLeivar Rico, Pablo
dc.contributor.authorChi, Jordi
dc.contributor.authorCova, Marta
dc.contributor.authorDe las Rivas, Matilde
dc.contributor.authorMedina, Ana
dc.contributor.authorJunqueira Borges, Rafael
dc.contributor.authorUsón, Isabel
dc.contributor.authorHurtado-Guerrero, Ramón
dc.contributor.authorIzquierdo, Luis
dc.date.accessioned2022-05-09T15:19:59Z
dc.date.accessioned2023-07-13T05:43:28Z
dc.date.available2022-05-09T15:19:59Z
dc.date.available2023-07-13T05:43:28Z
dc.date.issued2020-10
dc.identifier.urihttp://hdl.handle.net/20.500.14342/968
dc.description.abstractABSTRACT UDP-N-acetylglucosamine (UDP-GlcNAc), the main product of the hexosamine biosynthetic pathway, is an important metabolite in protozoan parasites since its sugar moiety is incorporated into glycosylphosphatidylinositol (GPI) glycolipids and N- and O-linked glycans. Apicomplexan parasites have a hexosamine pathway comparable to other eukaryotic organisms, with the exception of the glucosamine-phosphate N-acetyltransferase (GNA1) enzymatic step that has an independent evolutionary origin and significant differences from nonapicomplexan GNA1s. By using conditional genetic engineering, we demonstrate the requirement of GNA1 for the generation of a pool of UDP-GlcNAc and for the development of intraerythrocytic asexual Plasmodium falciparum parasites. Furthermore, we present the 1.95 Å resolution structure of the GNA1 ortholog from Cryptosporidium parvum, an apicomplexan parasite which is a leading cause of diarrhea in developing countries, as a surrogate for P. falciparum GNA1. The in-depth analysis of the crystal shows the presence of specific residues relevant for GNA1 enzymatic activity that are further investigated by the creation of site-specific mutants. The experiments reveal distinct features in apicomplexan GNA1 enzymes that could be exploitable for the generation of selective inhibitors against these parasites, by targeting the hexosamine pathway. This work underscores the potential of apicomplexan GNA1 as a drug target against malaria.eng
dc.description.abstractIMPORTANCE Apicomplexan parasites cause a major burden on global health and economy. The absence of treatments, the emergence of resistances against available therapies, and the parasite’s ability to manipulate host cells and evade immune systems highlight the urgent need to characterize new drug targets to treat infections caused by these parasites. We demonstrate that glucosamine-6-phosphate N-acetyltransferase (GNA1), required for the biosynthesis of UDP-N-acetylglucosamine (UDP-GlcNAc), is essential for P. falciparum asexual blood stage development and that the disruption of the gene encoding this enzyme quickly causes the death of the parasite within a life cycle. The high-resolution crystal structure of the GNA1 ortholog from the apicomplexan parasite C. parvum, used here as a surrogate, highlights significant differences from human GNA1. These divergences can be exploited for the design of specific inhibitors against the malaria parasite.eng
dc.format.extent15 p.cat
dc.language.isoengcat
dc.publisherAmerican Society for Microbiologycat
dc.relation.ispartofMolecular Biology and Physiology. Vol.11, n.5 (2020), e02045-20cat
dc.rightsAttribution 4.0 International
dc.rights© L'autor/a
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceRECERCAT (Dipòsit de la Recerca de Catalunya)
dc.subject.otherMalàriacat
dc.subject.otherMetabolismecat
dc.subject.otherParàsitscat
dc.subject.otherMalariacat
dc.subject.otherMetabolismcat
dc.subject.otherPlasmodium falciparumcat
dc.subject.otherUDP-N-acetylglucosaminecat
dc.subject.otherAminosugar pathwaycat
dc.subject.otherApicomplexan parasitescat
dc.titlePlasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage developmentcat
dc.typeinfo:eu-repo/semantics/articlecat
dc.typeinfo:eu-repo/semantics/publishedVersioncat
dc.rights.accessLevelinfo:eu-repo/semantics/openAccess
dc.embargo.termscapcat
dc.subject.udc616.9
dc.identifier.doihttps://doi.org/10.1128/mBio.02045-20cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MCI/Centro de Excelencia Severo Ochoa 2019-2023 Program/CEX2018-000806-Scat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO i FEDER/PN I+D/SAF2016-76080-Rcat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MCI/PN I+D/PID2019-110810RB-I00cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MCI i FEDER/PN I+D/PGC2018-101370-B-I00cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MCI i FEDER/PN I+D/MDM2014-0435-01cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MCI/PN I+D/BES-2017-080368cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MCI/PN I+D/FAPESP 2016/24191-8cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MEC/PN I+D/CTQ2013-44367-C2-2-Pcat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MEC/PN I+D/BFU2016-75633-Pcat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MEC/PN I+D/PID2019-105451GB-I00cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/MSCA ITN/Grant No. 608295cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Aragón i FEDER/E34_R17cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Aragón i FEDER/LMP58_18cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/Grant No. 283570cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/Grant No. 5186cat
dc.relation.projectIDinfo:eu-repo/grantAgreement/MCI/PN I+D/BFU2016-77427cat


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