A genomic glimpse of aminoacyl-tRNA synthetases in malaria parasite Plasmodium falciparum

Abstract

BackgroundPlasmodium parasites are causative agents of malaria which affects >500 million people and claims ~2 million lives annually. The completion of Plasmodium genome sequencing and availability of PlasmoDB database has provided a platform for systematic study of parasite genome. Aminoacyl-tRNA synthetases (aaRSs) are pivotal enzymes for protein translation and other vital cellular processes. We report an extensive analysis of the Plasmodium falciparum genome to identify and classify aaRSs in this organism.ResultsUsing various computational and bioinformatics tools, we have identified 37 aaRSs in P. falciparum. Our key observations are: (i) fraction of proteome dedicated to aaRSs in P. falciparum is very high compared to many other organisms; (ii) 23 out of 37 Pf-aaRS sequences contain signal peptides possibly directing them to different cellular organelles; (iii) expression profiles of Pf-aaRSs vary considerably at various life cycle stages of the parasite; (iv) several PfaaRSs posses very unusual domain architectures; (v) phylogenetic analyses reveal evolutionary relatedness of several parasite aaRSs to bacterial and plants aaRSs; (vi) three dimensional structural modelling has provided insights which could be exploited in inhibitor discovery against parasite aaRSs.ConclusionWe have identified 37 Pf-aaRSs based on our bioinformatics analysis. Our data reveal several unique attributes in this protein family. We have annotated all 37 Pf-aaRSs based on predicted localization, phylogenetics, domain architectures and their overall protein expression profiles. The sets of distinct features elaborated in this work will provide a platform for experimental dissection of this family of enzymes, possibly for the discovery of novel drugs against malaria.

Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses

“…The overall fold of PfTyrRS is typical of class I synthetases 3,4 and comprises a catalytic domain (residues 18-260, Rossmann fold) and an anti-codon-binding domain (residues 261-370). Human mitochondrial and malaria parasite apicoplastic TyrRS belong to bacterial lineage, whereas human cytoplasmic TyrRS and PfTyrRS belong to a separate eukaryotic group 6,29 ( Fig. 2c).…”

“…Numerous studies have shown that members of this enzyme family are quite adept at 'moonlighting' in terms of possessing extra capabilities that widen their biological attributes [5][6][7][8] . Studies have indicated that human tyrosyl-, tryptophanyl-and lysyl-tRNA synthetases can be secreted extracellularly and can mimic cytokines [5][6][7][8] .…”

“…Numerous studies have shown that members of this enzyme family are quite adept at 'moonlighting' in terms of possessing extra capabilities that widen their biological attributes [5][6][7][8] . Studies have indicated that human tyrosyl-, tryptophanyl-and lysyl-tRNA synthetases can be secreted extracellularly and can mimic cytokines [5][6][7][8] . For these extra roles, the human TyrRS and TrpRS require either proteolytic cleavage or alternate splicing to become active [5][6][7][8][9] , whereas LysRS can act like a cytokine without processing 44 .…”

“…Studies have indicated that human tyrosyl-, tryptophanyl-and lysyl-tRNA synthetases can be secreted extracellularly and can mimic cytokines [5][6][7][8] . For these extra roles, the human TyrRS and TrpRS require either proteolytic cleavage or alternate splicing to become active [5][6][7][8][9] , whereas LysRS can act like a cytokine without processing 44 . In this light, this is the first report of a human pathogen tRNA synthetase that can also perform moonlighting activity of inducing host immune system to release proinflammatory cytokines.…”

“…PfTyrRS was predicted to be cytoplasmic whereas PfTyrRS api is probably targeted to the parasite apicoplast 6 . Here we have investigated the structural, immunological and spatial localization attributes of PfTyrRS.…”