Aminoacyl tRNA synthetases as malarial drug targets: a comparative bioinformatics study

Abstract

BackgroundTreatment of parasitic diseases has been challenging due to evolution of drug resistant parasites, and thus there is need to identify new class of drugs and drug targets. Protein translation is important for survival of malarial parasite, Plasmodium, and the pathway is present in all of its life cycle stages. Aminoacyl tRNA synthetases are primary enzymes in protein translation as they catalyse amino acid addition to the cognate tRNA. This study sought to understand differences between Plasmodium and human aminoacyl tRNA synthetases through bioinformatics analysis.MethodsPlasmodium berghei, Plasmodium falciparum, Plasmodium fragile, Plasmodium knowlesi, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, Plasmodium yoelii and human aminoacyl tRNA synthetase sequences were retrieved from UniProt database and grouped into 20 families based on amino acid specificity. These families were further divided into two classes. Both families and classes were analysed. Motif discovery was carried out using the MEME software, sequence identity calculation was done using an in-house Python script, multiple sequence alignments were performed using PROMALS3D and TCOFFEE tools, and phylogenetic tree calculations were performed using MEGA vs 7.0 tool. Possible alternative binding sites were predicted using FTMap webserver and SiteMap tool.ResultsMotif discovery revealed Plasmodium-specific motifs while phylogenetic tree calculations showed that Plasmodium proteins have different evolutionary history to the human homologues. Human aaRSs sequences showed low sequence identity (below 40%) compared to Plasmodium sequences. Prediction of alternative binding sites revealed potential druggable sites in PfArgRS, PfMetRS and PfProRS at regions that are weakly conserved when compared to the human homologues. Multiple sequence analysis, motif discovery, pairwise sequence identity calculations and phylogenetic tree analysis showed significant differences between parasite and human aaRSs proteins despite functional and structural conservation. These differences may provide a basis for further exploration of Plasmodium aminoacyl tRNA synthetases as potential drug targets.ConclusionThis study showed that, despite, functional and structural conservation, Plasmodium aaRSs have key differences from the human homologues. These differences in Plasmodium aaRSs can be targeted to develop anti-malarial drugs with less toxicity to the host.Electronic supplementary materialThe online version of this article (10.1186/s12936-019-2665-6) contains supplementary material, which is available to authorized users.

Characterisation of plasmodial transketolases and identification of potential inhibitors: an in silico study

“…On calculation of phylogenetic tree, the clustering based on eighteen TKT sequences agreed with all versus all sequence identity clustering as shown in Fig. 3 c. A similar observation was previously shown in other families [ 57 , 58 ]. Four clades viz I, II, III and IV were observed.…”

“…3c. A similar observation was previously shown in other families [57,58]. Four clades viz I, II, III and IV were observed.…”

Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

“…Discovery and analysis of motifs was performed according to methodology by Ross et al and Nyamai and Tastan Bishop [56,86] with slight modification using the retrieved sequences as a query. Briefly, motif discovery was performed using online MEME SUITE version 5.05 [55], using the 0-order model of sequences.…”

Novel chloroquine loaded curcumin based anionic linear globular dendrimer G2: a metabolomics study on Plasmodium falciparum in vitro using 1H NMR spectroscopy

“…Another metabolic pathway modified by synthesized NDC-CQ was aminoacyl-tRNA biosynthesis. According to the study of Nyamai and Tastan Bishop (2019), this metabolic pathway in addition to synthesizing the first enzyme required for protein translation and amino acid catalysis, is different in humans and the parasite Plasmodium . Therefore, it is considered as a suitable drug target for antimalarial drug development.…”