Peculiarities of aminoacyl-tRNA synthetases from trypanosomatids

Parrot, Camila; Moulinier, Luc; Bernard, Florian; Hashem, Yaser; Dupuy, Denis

doi:10.1016/j.jbc.2021.100913

Cited by 9 publications

(10 citation statements)

References 75 publications

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“…Apart from the technical considerations, our observations raise the question of the functional significance of the presence of this stem-loop structure at the extremity of all C. elegans SL variants. It has been previously observed that potential stem-loop structures adjacent to the cap are widespread in the Spliced Leaders of phylogenetically divergent species although the sequence of the self-complementarity itself is not conserved 24 . We confirmed the same strand bias in Leishmania Tarentolae direct-cDNA sequencing experiments 24 , and it is likely that similar library behavior will extend to all species using trans -splicing.…”

Section: Discussionmentioning

confidence: 99%

Quantitative analysis of C. elegans transcripts by Nanopore direct-cDNA sequencing reveals terminal hairpins in non trans-spliced mRNAs

et al. 2023

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In nematodes and kinetoplastids, mRNA processing involves a trans-splicing step through which a short sequence from a snRNP replaces the original 5’ end of the primary transcript. It has long been held that 70% of C. elegans mRNAs are submitted to trans-splicing. Our recent work suggested that the mechanism is more pervasive but not fully captured by mainstream transcriptome sequencing methods. Here we use Oxford Nanopore’s long-read amplification-free sequencing technology to perform a comprehensive analysis of trans-splicing in worms. We demonstrate that spliced leader (SL) sequences at the 5’ end of the mRNAs affect library preparation and generate sequencing artefacts due to their self-complementarity. Consistent with our previous observations, we find evidence of trans-splicing for most genes. However, a subset of genes appears to be only marginally trans-spliced. These mRNAs all share the capacity to generate a 5’ terminal hairpin structure mimicking the SL structure and offering a mechanistic explanation for their non conformity. Altogether, our data provide a comprehensive quantitative analysis of SL usage in C. elegans.

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Section: Discussionmentioning

confidence: 99%

Quantitative analysis of C. elegans transcripts by Nanopore direct-cDNA sequencing reveals terminal hairpins in non trans-spliced mRNAs

et al. 2023

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“…Even though the structures of HF-bound Pf ProRS and Hs ProRS are identical, there are substantial differences in the interaction of some of the residues such as Thr478, terminal phosphate group of AMPPNP, water molecule, etc., which suggest that inhibitors of Pf ProRS, like quinazolinone, might also inhibit trypanosomal ProRS. Both cytosolic and mitochondrial ProRS isoforms in Leishmania contain the Ybak/ProX domain at the N-terminus (Figure ), which is a prokaryotic-type editing domain and helps in the rectification of mischarged tRNAs. , …”

Section: Research Accomplished On Trypanosomatid Aminoacyl Trna Synth...mentioning

confidence: 97%

“…In T. brucei , the lysyl tRNA synthetases are located in mitochondria as well as cytosol, and these isoforms are coded by distinct genes. 45 The mitochondrial LysRS has a C-terminus extension of 92–96 amino acids 46 ( Figure 4 ). In humans, LysRS was found to have a very strong interaction with multi-aaRSs complex (MARS).…”

Section: Research Accomplished On Trypanosomatid Aminoacyl Trna Synth...mentioning

confidence: 99%

“…It is noteworthy that the lysine rich regions have been observed to play an important role in tRNA binding. 46 The human HisRS also contains a WHEP domain in its N-terminal which could not be seen in trypanosomatids. The essentiality of histidyl tRNA synthetase for the survival of T. brucei is documented with the help of RNAi knockdown of the gene that led to a severe decrease in parasite growth rate.…”

Section: Research Accomplished On Trypanosomatid Aminoacyl Trna Synth...mentioning

confidence: 99%

“…Both cytosolic and mitochondrial ProRS isoforms in Leishmania contain the Ybak/ProX domain at the Nterminus (Figure 8), which is a prokaryotic-type editing domain and helps in the rectification of mischarged tRNAs. 28,46 6.11. Other tRNA Synthetases.…”

Section: Tryptophanyl Trna Synthetase (Trprs/wrs)mentioning

confidence: 99%

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Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites

Nasim

Qureshi

2023

ACS Omega

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The ensemble of aminoacyl tRNA synthetases is regarded as a key component of the protein translation machinery. With the progressive increase in structure-based studies on tRNA synthetase-ligand complexes, the detailed picture of these enzymes is becoming clear. Having known their critical role in deciphering the genetic code in a living system, they have always been chosen as one of the important targets for development of antimicrobial drugs. Later on, the role of aminoacyl tRNA synthetases (aaRSs) on the survivability of trypanosomatids has also been validated. It became evident through several gene knockout studies that targeting even one of these enzymes affected parasitic growth drastically. Such successful studies have inspired researchers to search for inhibitors that could specifically target trypanosomal aaRSs, and their never-ending efforts have provided fruitful results. Taking all such studies into consideration, these macromolecules of prime importance deserve further investigation for the development of drugs that cure spectrum of infections caused by trypanosomatids. In this review, we have compiled advancements of over a decade that have taken place in the pursuit of devising drugs by using trypanosomatid aaRSs as a major target of interest. Several of these inhibitors work on an exemplary low concentration range without posing any threat to the mammalian cells which is a very critical aspect of the drug discovery process. Advancements have been made in terms of using structural biology as an important tool to analyze the architecture of the trypanosomatids aaRSs and concoction of inhibitors with augmented specificities toward their targets. Some of the inhibitors that have been tested on other parasites successfully but their efficacy has so far not been validated against these trypanosomatids have also been appended.

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Strategies for Detecting Aminoacylation and Aminoacyl‐tRNA Editing In Vitro and In Cells

Watkins,

Kavoor,

Musier‐Forsyth

2024

Israel Journal of Chemistry

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Aminoacyl‐tRNA synthetases (aaRSs) maintain translational fidelity by ensuring the formation of correct aminoacyl‐tRNA pairs. Numerous point mutations in human aaRSs have been linked to disease phenotypes. Structural studies of aaRSs from human pathogens encoding unique domains support these enzymes as potential candidates for therapeutics. Studies have shown that the identity of tRNA pools in cells changes between different cell types and under stress conditions. While traditional radioactive aminoacylation analyses can determine the effect of disease‐causing mutations on aaRS function, these assays are not amenable to drug discovery campaigns and do not take into account the variability of the intracellular tRNA pools. Here, we review modern techniques to characterize aaRS activity in vitro and in cells. The cell‐based approaches analyse the aminoacyl‐tRNA pool to observe trends in aaRS activity and fidelity. Taken together, these approaches allow high‐throughput drug screening of aaRS inhibitors and systems‐level analyses of the dynamic tRNA population under a variety of conditions and disease states.

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Peculiarities of aminoacyl-tRNA synthetases from trypanosomatids

Cited by 9 publications

References 75 publications

Quantitative analysis of C. elegans transcripts by Nanopore direct-cDNA sequencing reveals terminal hairpins in non trans-spliced mRNAs

Quantitative analysis of C. elegans transcripts by Nanopore direct-cDNA sequencing reveals terminal hairpins in non trans-spliced mRNAs

Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites

Strategies for Detecting Aminoacylation and Aminoacyl‐tRNA Editing In Vitro and In Cells

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