Unusual domain architecture of aminoacyl tRNA synthetases and their paralogs from Leishmania major

Abstract

BackgroundLeishmania major, a protozoan parasite, is the causative agent of cutaneous leishmaniasis. Due to the development of resistance against the currently available anti-leishmanial drugs, there is a growing need for specific inhibitors and novel drug targets. In this regards, aminoacyl tRNA synthetases, the linchpins of protein synthesis, have received recent attention among the kinetoplastid research community. This is the first comprehensive survey of the aminoacyl tRNA synthetases, their paralogs and other associated proteins from L. major.ResultsA total of 26 aminoacyl tRNA synthetases were identified using various computational and bioinformatics tools. Phylogenetic analysis and domain architectures of the L. major aminoacyl tRNA synthetases suggest a probable archaeal/eukaryotic origin. Presence of additional domains or N- or C-terminal extensions in 11 aminoacyl tRNA synthetases from L. major suggests possibilities such as additional tRNA binding or oligomerization or editing activity. Five freestanding editing domains were identified in L. major. Domain assignment revealed a novel asparagine tRNA synthetase paralog, asparagine synthetase A which has been so far reported from prokaryotes and archaea.ConclusionsA comprehensive bioinformatic analysis revealed 26 aminoacyl tRNA synthetases and five freestanding editing domains in L. major. Identification of two EMAP (endothelial monocyte-activating polypeptide) II-like proteins similar to human EMAP II-like proteins suggests their participation in multisynthetase complex formation. While the phylogeny of tRNA synthetases suggests a probable archaeal/eukaryotic origin, phylogeny of asparagine synthetase A strongly suggests a bacterial origin. The unique features identified in this work provide rationale for designing inhibitors against parasite aminoacyl tRNA synthetases and their paralogs.

A Multiple Aminoacyl-tRNA Synthetase Complex That Enhances tRNA-Aminoacylation in African Trypanosomes

“…Analysis of the TriTryp (T. brucei, T. cruzi, and Leishmania) genome database did not identify any additional genes with a predicted aaRS domain. It did show that all 24 genes are highly conserved among the species in the TriTryp database and, although to a lesser extent, among other organisms, but they were more similar to genes for eukaryotic than prokaryotic enzymes, as observed for Leishmania (58). It is unlikely that such genes are gaps in all three databases, and thus, these 24 genes probably represent all aaRS genes in these organisms.…”

Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei

“…Trypanosomatids encode a full complement of both class 1 and class 2 aaRSs; bioinformatics analysis of Leishmania major (20) and T. brucei (21) identified 25 and 24 genes encoding canonical aaRS homologs, respectively, covering all key amino acids. Additionally, they encode three multiple-aaRS (MARS) complex-associated proteins (MCPs).…”

Identification and Functional Characterization of a Novel Bacterial Type Asparagine Synthetase A

“…Although they are eukaryotes, Leishmania and Trypanosoma surprisingly possess both ASNA (LmjF. 26.0830) and ASNB (LmjF.29.1490) (13).…”

“…1) (4). We had previously reported a novel asparagine-tRNA synthetase paralog, asparagine synthetase A from Leishmania major (13). These paralogs retain the typical aminoacyl-tRNA synthetase catalytic domain with class II motifs but are devoid of the anticodon binding domain (14).…”