The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic target

Apicomplexa form a phylum of obligate parasitic protozoa of great clinical and veterinary importance. These parasites synthesize glycoconjugates for their survival and infectivity, but the enzymatic steps required to generate the glycosylation precursors are not completely characterized. In particul...

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Autores: Cova, Marta, López Gutiérrez, Borja, Artigas Jerónimo, Sara, González Díaz, Aida, Bandini, Giulia, Maere, Steven, Carretero Paulet, Lorenzo, Izquierdo Lázaro, Luis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/121294
Acceso en línea:https://hdl.handle.net/2445/121294
Access Level:acceso abierto
Palabra clave:Glicòmica
Malalties parasitàries
Glycomics
Parasitic diseases
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spelling The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic targetCova, MartaLópez Gutiérrez, BorjaArtigas Jerónimo, SaraGonzález Díaz, AidaBandini, GiuliaMaere, StevenCarretero Paulet, LorenzoIzquierdo Lázaro, LuisGlicòmicaMalalties parasitàriesGlycomicsParasitic diseasesApicomplexa form a phylum of obligate parasitic protozoa of great clinical and veterinary importance. These parasites synthesize glycoconjugates for their survival and infectivity, but the enzymatic steps required to generate the glycosylation precursors are not completely characterized. In particular, glucosamine-phosphate N-acetyltransferase (GNA1) activity, needed to produce the essential UDP-N-acetylglucosamine (UDP-GlcNAc) donor, has not been identified in any Apicomplexa. We scanned the genomes of Plasmodium falciparum and representatives from six additional main lineages of the phylum for proteins containing the Gcn5-related N-acetyltransferase (GNAT) domain. One family of GNAT-domain containing proteins, composed by a P. falciparum sequence and its six apicomplexan orthologs, rescued the growth of a yeast temperature-sensitive GNA1 mutant. Heterologous expression and in vitro assays confirmed the GNA1 enzymatic activity in all lineages. Sequence, phylogenetic and synteny analyses suggest an independent origin of the Apicomplexa-specific GNA1 family, parallel to the evolution of a different GNA1 family in other eukaryotes. The inability to disrupt an otherwise modifiable gene target suggests that the enzyme is essential for P. falciparum growth. The relevance of UDP-GlcNAc for parasite viability, together with the independent evolution and unique sequence features of Apicomplexa GNA1, highlights the potential of this enzyme as a selective therapeutic target against apicomplexans.Macmillan2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/121294Articles publicats en revistes (ISGlobal)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: http://dx.doi.org/10.1038/s41598-018-22441-3Scientific Reports, 2018, vol. 8, num. 4005http://dx.doi.org/10.1038/s41598-018-22441-3info:eu-repo/grantAgreement/EC/FP7/608295cc by (c) Cova et al., 2018http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1212942026-05-27T06:46:51Z
dc.title.none.fl_str_mv The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic target
title The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic target
spellingShingle The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic target
Cova, Marta
Glicòmica
Malalties parasitàries
Glycomics
Parasitic diseases
title_short The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic target
title_full The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic target
title_fullStr The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic target
title_full_unstemmed The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic target
title_sort The Apicomplexa-specific glucosamine-6-phosphate N-acetyltransferase gene family encodes a key enzyme for glycoconjugate synthesis with potential as therapeutic target
dc.creator.none.fl_str_mv Cova, Marta
López Gutiérrez, Borja
Artigas Jerónimo, Sara
González Díaz, Aida
Bandini, Giulia
Maere, Steven
Carretero Paulet, Lorenzo
Izquierdo Lázaro, Luis
author Cova, Marta
author_facet Cova, Marta
López Gutiérrez, Borja
Artigas Jerónimo, Sara
González Díaz, Aida
Bandini, Giulia
Maere, Steven
Carretero Paulet, Lorenzo
Izquierdo Lázaro, Luis
author_role author
author2 López Gutiérrez, Borja
Artigas Jerónimo, Sara
González Díaz, Aida
Bandini, Giulia
Maere, Steven
Carretero Paulet, Lorenzo
Izquierdo Lázaro, Luis
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Glicòmica
Malalties parasitàries
Glycomics
Parasitic diseases
topic Glicòmica
Malalties parasitàries
Glycomics
Parasitic diseases
description Apicomplexa form a phylum of obligate parasitic protozoa of great clinical and veterinary importance. These parasites synthesize glycoconjugates for their survival and infectivity, but the enzymatic steps required to generate the glycosylation precursors are not completely characterized. In particular, glucosamine-phosphate N-acetyltransferase (GNA1) activity, needed to produce the essential UDP-N-acetylglucosamine (UDP-GlcNAc) donor, has not been identified in any Apicomplexa. We scanned the genomes of Plasmodium falciparum and representatives from six additional main lineages of the phylum for proteins containing the Gcn5-related N-acetyltransferase (GNAT) domain. One family of GNAT-domain containing proteins, composed by a P. falciparum sequence and its six apicomplexan orthologs, rescued the growth of a yeast temperature-sensitive GNA1 mutant. Heterologous expression and in vitro assays confirmed the GNA1 enzymatic activity in all lineages. Sequence, phylogenetic and synteny analyses suggest an independent origin of the Apicomplexa-specific GNA1 family, parallel to the evolution of a different GNA1 family in other eukaryotes. The inability to disrupt an otherwise modifiable gene target suggests that the enzyme is essential for P. falciparum growth. The relevance of UDP-GlcNAc for parasite viability, together with the independent evolution and unique sequence features of Apicomplexa GNA1, highlights the potential of this enzyme as a selective therapeutic target against apicomplexans.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/121294
url https://hdl.handle.net/2445/121294
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.1038/s41598-018-22441-3
Scientific Reports, 2018, vol. 8, num. 4005
http://dx.doi.org/10.1038/s41598-018-22441-3
info:eu-repo/grantAgreement/EC/FP7/608295
dc.rights.none.fl_str_mv cc by (c) Cova et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Cova et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Macmillan
publisher.none.fl_str_mv Macmillan
dc.source.none.fl_str_mv Articles publicats en revistes (ISGlobal)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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