Plasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage development
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1128/mBio.02045-20 http://hdl.handle.net/11449/205390 |
Resumo: | 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 Nand O-linked glycans. Apicomplexan parasites have a hexosamine pathway comparable to other eukaryotic organisms, with the exception of the glucosamine-phosphate Nacetyltransferase (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 indepth 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. IMPORTANCE 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. |
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Plasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage developmentAminosugar pathwayApicomplexan parasitesMalariaMetabolismPlasmodium falciparumUDP-N-acetylglucosamineUDP-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 Nand O-linked glycans. Apicomplexan parasites have a hexosamine pathway comparable to other eukaryotic organisms, with the exception of the glucosamine-phosphate Nacetyltransferase (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 indepth 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. IMPORTANCE 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.ISGlobal HospitalClinic–Universitat de BarcelonaInstitute of Biocomputation and Physics of Complex Systems (BIFI) University of ZaragozaCrystallographic Methods Institute of Molecular Biology of Barcelona (IBMB–CSIC)Departamento de Física e Biofísica Instituto de Biociências Universidade Estadual Paulista (UNESP)Laboratory of Biochemistry Institut Químic de Sarrià Universitat Ramon LlullICREA Institució Catalana de Recerca i Estudis AvançatsCopenhagen Center for Glycomics Department of Cellular and Molecular Medicine School of Dentistry University of CopenhagenLaboratorio de Microscopías Avanzada (LMA) University of ZaragozaFundación ARAIDDepartamento de Física e Biofísica Instituto de Biociências Universidade Estadual Paulista (UNESP)HospitalClinic–Universitat de BarcelonaUniversity of ZaragozaInstitute of Molecular Biology of Barcelona (IBMB–CSIC)Universidade Estadual Paulista (Unesp)Universitat Ramon LlullInstitució Catalana de Recerca i Estudis AvançatsSchool of Dentistry University of CopenhagenFundación ARAIDChi, JordiCova, MartaDe Las Rivas, MatildeMedina, AnaJunqueira Borges, Rafael [UNESP]Leivar, PabloPlanas, AntoniUsón, IsabelHurtado-Guerrero, RamónIzquierdo, Luis2021-06-25T10:14:32Z2021-06-25T10:14:32Z2020-09-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1-15http://dx.doi.org/10.1128/mBio.02045-20mBio, v. 11, n. 5, p. 1-15, 2020.2150-75112161-2129http://hdl.handle.net/11449/20539010.1128/mBio.02045-202-s2.0-85094171493Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengmBioinfo:eu-repo/semantics/openAccess2021-10-23T12:40:00Zoai:repositorio.unesp.br:11449/205390Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T21:13:49.114814Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Plasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage development |
title |
Plasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage development |
spellingShingle |
Plasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage development Chi, Jordi Aminosugar pathway Apicomplexan parasites Malaria Metabolism Plasmodium falciparum UDP-N-acetylglucosamine |
title_short |
Plasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage development |
title_full |
Plasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage development |
title_fullStr |
Plasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage development |
title_full_unstemmed |
Plasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage development |
title_sort |
Plasmodium falciparum apicomplexan-specific glucosamine-6-phosphate n-acetyltransferase is key for amino sugar metabolism and asexual blood stage development |
author |
Chi, Jordi |
author_facet |
Chi, Jordi Cova, Marta De Las Rivas, Matilde Medina, Ana Junqueira Borges, Rafael [UNESP] Leivar, Pablo Planas, Antoni Usón, Isabel Hurtado-Guerrero, Ramón Izquierdo, Luis |
author_role |
author |
author2 |
Cova, Marta De Las Rivas, Matilde Medina, Ana Junqueira Borges, Rafael [UNESP] Leivar, Pablo Planas, Antoni Usón, Isabel Hurtado-Guerrero, Ramón Izquierdo, Luis |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
HospitalClinic–Universitat de Barcelona University of Zaragoza Institute of Molecular Biology of Barcelona (IBMB–CSIC) Universidade Estadual Paulista (Unesp) Universitat Ramon Llull Institució Catalana de Recerca i Estudis Avançats School of Dentistry University of Copenhagen Fundación ARAID |
dc.contributor.author.fl_str_mv |
Chi, Jordi Cova, Marta De Las Rivas, Matilde Medina, Ana Junqueira Borges, Rafael [UNESP] Leivar, Pablo Planas, Antoni Usón, Isabel Hurtado-Guerrero, Ramón Izquierdo, Luis |
dc.subject.por.fl_str_mv |
Aminosugar pathway Apicomplexan parasites Malaria Metabolism Plasmodium falciparum UDP-N-acetylglucosamine |
topic |
Aminosugar pathway Apicomplexan parasites Malaria Metabolism Plasmodium falciparum UDP-N-acetylglucosamine |
description |
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 Nand O-linked glycans. Apicomplexan parasites have a hexosamine pathway comparable to other eukaryotic organisms, with the exception of the glucosamine-phosphate Nacetyltransferase (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 indepth 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. IMPORTANCE 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. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-09-01 2021-06-25T10:14:32Z 2021-06-25T10:14:32Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1128/mBio.02045-20 mBio, v. 11, n. 5, p. 1-15, 2020. 2150-7511 2161-2129 http://hdl.handle.net/11449/205390 10.1128/mBio.02045-20 2-s2.0-85094171493 |
url |
http://dx.doi.org/10.1128/mBio.02045-20 http://hdl.handle.net/11449/205390 |
identifier_str_mv |
mBio, v. 11, n. 5, p. 1-15, 2020. 2150-7511 2161-2129 10.1128/mBio.02045-20 2-s2.0-85094171493 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
mBio |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
1-15 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808129299471925248 |