Protein translation in Plasmodium parasites

Jackson, Katherine M.; Habib, Saman; Frugier, Magali; Hoen, Rob; Khan, Sameena; Pham, James S.; Pouplana, Lluı́s Ribas de; Royo, Míriam; Santos, Manuel A. S.; Sharma, Amit; Ralph, Stuart A.

doi:10.1016/j.pt.2011.05.005

Cited by 85 publications

(96 citation statements)

References 94 publications

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“…In Plasmodium and Toxoplasma, RNA translation takes place in three subcellular compartments: the parasite cytosol, the single tubular mitochondrion, and a relict plastid called the apicoplast (14). While thousands of genes encoded in Apicomplexa genomes are translated in the cytoplasm, fewer than 50 are translated in the apicoplast and only 3 are translated in the mitochondrion.…”

Section: Translation In the Parasite Mitochondria And Apicoplastmentioning

confidence: 99%

Translational Control in Plasmodium and Toxoplasma Parasites

et al. 2013

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The life cycles of apicomplexan parasites such as Plasmodium spp. and Toxoplasma gondii are complex, consisting of proliferative and latent stages within multiple hosts. Dramatic transformations take place during the cycles, and they demand precise control of gene expression at all levels, including translation. This review focuses on the mechanisms that regulate translational control in Plasmodium and Toxoplasma, with a particular emphasis on the phosphorylation of the ␣ subunit of eukaryotic translation initiation factor 2 (eIF2␣). Phosphorylation of eIF2␣ (eIF2␣ϳP) is a conserved mechanism that eukaryotic cells use to repress global protein synthesis while enhancing gene-specific translation of a subset of mRNAs. Elevated levels of eIF2␣ϳP have been observed during latent stages in both Toxoplasma and Plasmodium, indicating that translational control plays a role in maintaining dormancy. Parasite-specific eIF2␣ kinases and phosphatases are also required for proper developmental transitions and adaptation to cellular stresses encountered during the life cycle. Identification of small-molecule inhibitors of apicomplexan eIF2␣ kinases may selectively interfere with parasite translational control and lead to the development of new therapies to treat malaria and toxoplasmosis.

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Section: Translation In the Parasite Mitochondria And Apicoplastmentioning

confidence: 99%

Translational Control in Plasmodium and Toxoplasma Parasites

et al. 2013

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“…The aaRSs are known to incorporate additional domains that deploy the aaRSs for different noncanonical functions (12). Plasmodium falciparum possesses 36 aaRSs, which show asymmetric distributions among parasite organelles (7,8,13,14). The presence of appended domains imparts characteristic functions to parasite aaRSs (13-15).…”

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confidence: 99%

“…Plasmodium falciparum possesses 36 aaRSs, which show asymmetric distributions among parasite organelles (7,8,13,14). The presence of appended domains imparts characteristic functions to parasite aaRSs (13)(14)(15). For example, recent studies have revealed cytokine-like functions for malaria tyrosyl-tRNA synthetase (tyrosyl-RS) (15).…”

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confidence: 99%

Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases

Hussain

Yogavel

Sharma

2015

Antimicrob Agents Chemother

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Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes that couple cognate tRNAs with amino acids to transmit genomic information for protein translation. The Plasmodium falciparum nuclear genome encodes two P. falciparum methionyl-tRNA synthetases (PfMRS), termed PfMRS cyt and PfMRS api . Phylogenetic analyses revealed that the two proteins are of primitive origin and are related to heterokonts (PfMRS cyt ) or proteobacteria/primitive bacteria (PfMRS api ). We show that PfMRS cyt localizes in parasite cytoplasm, while PfMRS api localizes to apicoplasts in asexual stages of malaria parasites. Two known bacterial MRS inhibitors, REP3123 and REP8839, hampered Plasmodium growth very effectively in the early and late stages of parasite development. Small-molecule drug-like libraries were screened against modeled PfMRS structures, and several "hit" compounds showed significant effects on parasite growth. We then tested the effects of the hit compounds on protein translation by labeling nascent proteins with 35 S-labeled cysteine and methionine. Three of the tested compounds reduced protein synthesis and also blocked parasite growth progression from the ring stage to the trophozoite stage. Drug docking studies suggested distinct modes of binding for the three compounds, compared with the enzyme product methionyl adenylate. Therefore, this study provides new targets (PfMRSs) and hit compounds that can be explored for development as antimalarial drugs. P lasmodium falciparum is the most virulent form of Plasmodium and a causative agent of malaria. The World Health Organization (WHO) estimates that there are ϳ0.62 million deaths due to malaria per year (1). The P. falciparum genome is AT-rich (81%) and codes for ϳ5,300 proteins, with unusual distributions of several residues (2). Almost 60% of encoded proteins appear to be unique to the parasite, reflecting great evolutionary distance between the parasite and the genomes of known eukaryotes (3). The malaria parasite (and the related apicomplexan Toxoplasma gondii) has three translationally active compartments, i.e., cytoplasm, apicoplasts, and mitochondria (4-8). All malaria parasite proteins involved in the protein synthesis machinery are encoded by the nuclear genome. Either these proteins are transported to target organelles or their modified/activated substrates are transported across the organelles to perform required functions (4-9). The primary enzymes responsible for translating genetic code into polypeptide chains are aminoacyl-tRNA synthetases (aaRSs). The canonical function of aaRSs is to ligate a specific amino acid to its cognate tRNA, which is then employed in protein synthesis. The aaRSs are an ancient class of essential enzymes, and their catalytic domains are conserved in all kingdoms (bacteria, archaebacteria, and eukaryotes). On the basis of catalytic domain architecture, aaRSs are classified into two categories, with each class containing ϳ10 aaRSs (10). Although aaRSs perform the basic function of charging tRNA molecules for protein synthesis, a...

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“…The apicoplast is an attractive drug target because it is essential to both blood and liver stage parasites (18,19), harbors several metabolic pathways absent in the host, and its transcriptional and translational machinery are of bacterial origin. The apicoplast's indirect aminoacylation pathway is probably essential in malaria parasites because the parasite genome does not encode an apicoplast-targeted GlnRS (57,58,85). PfGluRS, the first enzyme in the apicoplast's indirect aminoacylation pathway, was refractory to gene deletion and is therefore essential for blood stage development (23).…”

Section: Discussionmentioning

confidence: 99%