Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery.
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ABSTRACT:
SUBMITTER: Pang L
PROVIDER: S-EPMC7916415 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery.
Pang Luping L Weeks Stephen D SD Van Aerschot Arthur A
International journal of molecular sciences 20210210 4
Aminoacyl-tRNA synthetases (aaRSs) catalyze the esterification of tRNA with a cognate amino acid and are essential enzymes in all three kingdoms of life. Due to their important role in the translation of the genetic code, aaRSs have been recognized as suitable targets for the development of small molecule anti-infectives. In this review, following a concise discussion of aaRS catalytic and proof-reading activities, the various inhibitory mechanisms of reported natural and synthetic aaRS inhibito ...[more]
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Project description: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.
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Project description:Aminoacyl-tRNA synthetases (AaRSs) are enzymes that catalyze the ligation of tRNAs to amino acids. There are AaRSs specific for each amino acid in the cell. Each cellular compartment in which translation takes place (the cytosol, mitochondria, and plastids in most cases), needs the full set of AaRSs; however, individual AaRSs can function in multiple compartments due to dual (or even multiple) targeting of nuclear-encoded proteins to various destinations in the cell. We searched the genomes of the chromerids, Chromera velia and Vitrella brassicaformis, for AaRS genes: 48 genes encoding AaRSs were identified in C. velia, while only 39 AaRS genes were found in V. brassicaformis. In the latter alga, ArgRS and GluRS were each encoded by a single gene occurring in a single copy; only PheRS was found in three genes, while the remaining AaRSs were encoded by two genes. In contrast, there were nine cases for which C. velia contained three genes of a given AaRS (45% of the AaRSs), all of them representing duplicated genes, except AsnRS and PheRS, which are more likely pseudoparalogs (acquired via horizontal or endosymbiotic gene transfer). Targeting predictions indicated that AaRSs are not (or not exclusively), in most cases, used in the cellular compartment from which their gene originates. The molecular phylogenies of the AaRSs are variable between the specific types, and similar between the two investigated chromerids. While genes with eukaryotic origin are more frequently retained, there is no clear pattern of orthologous pairs between C. velia and V. brassicaformis.
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Project description:BackgroundAminoacyl tRNA synthetases (aaRSs) constitute an essential enzyme super-family, providing fidelity of the translation process of mRNA to proteins in living cells. They are common to all kingdoms and are of utmost importance to all organisms. It is thus of great interest to understand the evolutionary relationships among them and underline signature motifs defining their common domains.ResultsWe utilized the Common Peptides (CPs) framework, based on extracted deterministic motifs from all aaRSs, to study family-specific properties. We identified novel aaRS-class related signatures that may supplement the current classification methods and provide a basis for identifying functional regions specific to each aaRS class. We exploited the space spanned by the CPs in order to identify similarities between aaRS families that are not observed using sequence alignment methods, identifying different inter-aaRS associations across different kingdom of life. We explored the evolutionary history of the aaRS families and evolutionary origins of the mitochondrial aaRSs. Lastly, we showed that prevalent CPs significantly overlap known catalytic and binding sites, suggesting that they have meaningful functional roles, as well as identifying a motif shared between aaRSs and a the Biotin-[acetyl-CoA carboxylase] synthetase (birA) enzyme overlapping binding sites in both families.ConclusionsThe study presents the multitude of ways to exploit the CP framework in order to extract meaningful patterns from the aaRS super-family. Specific CPs, discovered in this study, may play important roles in the functionality of these enzymes. We explored the evolutionary patterns in each aaRS family and tracked remote evolutionary links between these families.
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