Autor/a:
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Cova, Marta; López Gutiérrez, Borja; Artigas Jerónimo, Sara; González Díaz, Aida; Bandini, Giulia; Maere, Steven; Carretero Paulet, Lorenzo; Izquierdo, Luis
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Abstract:
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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. |