Uneven spread of cis- and trans-editing aminoacyl-tRNA synthetase domains within translational compartments of P. falciparum

Abstract

Accuracy of aminoacylation is dependent on maintaining fidelity during attachment of amino acids to cognate tRNAs. Cis- and trans-editing protein factors impose quality control during protein translation, and 8 of 36 Plasmodium falciparum aminoacyl-tRNA synthetase (aaRS) assemblies contain canonical putative editing modules. Based on expression and localization profiles of these 8 aaRSs, we propose an asymmetric distribution between the parasite cytoplasm and its apicoplast of putative editing-domain containing aaRSs. We also show that the single copy alanyl- and threonyl-tRNA synthetases are dually targeted to parasite cytoplasm and apicoplast. This bipolar presence of two unique synthetases presents opportunity for inhibitor targeting their aminoacylation and editing activities in twin parasite compartments. We used this approach to identify specific inhibitors against the alanyl- and threonyl-tRNA synthetases. Further development of such inhibitors may lead to anti-parasitics which simultaneously block protein translation in two key parasite organelles, a strategy of wider applicability for pathogen control.

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

“…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)(5)(6)(7)(8). All malaria parasite proteins involved in the protein synthesis machinery are encoded by the nuclear genome.…”

“…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).…”

“…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)(5)(6)(7)(8)(9). The primary enzymes responsible for translating genetic code into polypeptide chains are aminoacyl-tRNA synthetases (aaRSs).…”

The growing pipeline of natural aminoacyl-tRNA synthetase inhibitors for malaria treatment

“…Genomic and immunohistochemical evidence suggests that ThrRS is simultaneously targeted to both the cytoplasm and the apicoplast. 26 Jackson et al 27 showed that ThrRS is expressed throughout parasite blood-stage sexual development, and that borrelidin causes a rapid arrest of parasitic growth. Borrelidin is more active than mupirocin, which specifically targets the apicoplastic but not cytoplasmic IleRS isozyme, leading to the 'delayed death' phenotype associated with inhibitors of crucial apicoplast enzymes in plasmodium species.…”

“…Alanyl-, glycyl-, cysteinyl-and threonyl-tRNA synthetases (AlaRS, GlyRS, CysRS and ThrRS) are especially interesting potential targets due to their dual localization. [26][27][28] The natural macrolide antibiotic borrelidin was first isolated from Streptomyces rocheii in 1949, and its potent inhibitory activity against bacterial growth was later linked to ThrRS inhibition. 29 Borrelidin was more recently recovered from a largescale screen of soil microorganism-derived substances for its ability to block malaria parasite growth in vitro and in vivo.…”