Genetic Validation of
            <i>Leishmania donovani</i>
            Lysyl-tRNA Synthetase Shows that It Is Indispensable for Parasite Growth and Infectivity

Chadha, Sanya; Mallampudi, N. Arjunreddy; Mohapatra, Debendra K.; Madhubala, Rentala

doi:10.1128/mspheredirect.00340-17

Cited by 9 publications

(5 citation statements)

References 40 publications

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“…The KMSKS motif is replaced by KKIKT, and unlike Pyrococcus horikoshii ArgRS [27], the first lysine residue of this motif, Lys491, interacted with the adenine of ATP, suggesting its role in ATP-PPi exchange reaction. We also synthesized ATP resembling inhibitors knowing that analogs of ATP such as cladosporin are potent inhibitors of aaRSs [54,55]. Of them, the ones that possessed halogen groups attached to the para position or methyl groups linked to the ortho and meta positions of the third benzene ring augmented their potency.…”

Section: Discussionmentioning

confidence: 99%

Unraveling the peculiarities and development of novel inhibitors of leishmanial arginyl‐tRNA synthetase

Nasim,

Kumar,

Alvala

et al. 2024

The FEBS Journal

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Aminoacylation by tRNA synthetase is a crucial part of protein synthesis and is widely recognized as a therapeutic target for drug development. Unlike the arginyl‐tRNA synthetases (ArgRSs) reported previously, here, we report an ArgRS of Leishmania donovani (LdArgRS) that can follow the canonical two‐step aminoacylation process. Since a previously uncharacterized insertion region is present within its catalytic domain, we implemented the splicing by overlap extension PCR (SOE–PCR) method to create a deletion mutant (ΔIns‐LdArgRS) devoid of this region to investigate its function. Notably, the purified LdArgRS and ΔIns‐LdArgRS exhibited different oligomeric states along with variations in their enzymatic activity. The full‐length protein showed better catalytic efficiency than ΔIns‐LdArgRS, and the insertion region was identified as the tRNA binding domain. In addition, a benzothiazolo‐coumarin derivative (Comp‐7j) possessing high pharmacokinetic properties was recognized as a competitive and more specific inhibitor of LdArgRS than its human counterpart. Removal of the insertion region altered the mode of inhibition for ΔIns‐LdArgRS and caused a reduction in the inhibitor's binding affinity. Both purified proteins depicted variances in the secondary structural content upon ligand binding and thus, thermostability. Apart from the trypanosomatid‐specific insertion and Rossmann fold motif, LdArgRS revealed typical structural characteristics of ArgRSs, and Comp‐7j was found to bind within the ATP binding pocket. Furthermore, the placement of tRNAArg near the insertion region enhanced the stability and compactness of LdArgRS compared to other ligands. This study thus reports a unique ArgRS with respect to catalytic as well as structural properties, which can be considered a plausible drug target for the derivation of novel anti‐leishmanial agents.

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Section: Discussionmentioning

confidence: 99%

Unraveling the peculiarities and development of novel inhibitors of leishmanial arginyl‐tRNA synthetase

Nasim,

Kumar,

Alvala

et al. 2024

The FEBS Journal

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“…This study also reported the 3D structure of C. parvum LysRS in complex with cladosporin and L-Lys. LysRS-1 (KRS-1) from L. donovani is an essential gene ( 53 ).…”

Section: Inhibitors Against Parasite Aminoacyl-trna Synthetasesmentioning

confidence: 99%

Exploration of aminoacyl-tRNA synthetases from eukaryotic parasites for drug development

Gill

Sharma

2023

Journal of Biological Chemistry

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“…Furthermore, cladosporin could retard parasite growth proving that the LysRS gene is indeed essential for its survival. 50 …”

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

confidence: 99%

“…Thus, it can be exploited for the development of antitrypanosomal drugs, keeping in mind the differences present in the two residues present in the ATP binding pocket. Furthermore, cladosporin could retard parasite growth proving that the LysRS gene is indeed essential for its survival …”

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

confidence: 99%

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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Genetic Validation of Leishmania donovani Lysyl-tRNA Synthetase Shows that It Is Indispensable for Parasite Growth and Infectivity

Cited by 9 publications

References 40 publications

Unraveling the peculiarities and development of novel inhibitors of leishmanial arginyl‐tRNA synthetase

Unraveling the peculiarities and development of novel inhibitors of leishmanial arginyl‐tRNA synthetase

Exploration of aminoacyl-tRNA synthetases from eukaryotic parasites for drug development

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

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