Effects of Trypanosoma brucei tryptophanyl-tRNA synthetases silencing by RNA interference

García, Liliana Torcoroma; Leite, Ney Ribeiro; Alfonzo, Juan D.; Thiemann, Otávio Henrique

doi:10.1590/s0074-02762007005000090

Cited by 4 publications

(4 citation statements)

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“…These results suggest a possible activation of an early apoptosis mechanism that rapidly progresses to late apoptosis (positive SYTOX plus positive Annexin V) accompanied by DNA fragmentation. In trypanosomatids like Leishmania donovani, T. brucei , and T. cruzi, these same characteristics have been reported in parasites suffering calcium imbalance and oxidative stress (by ROS) [ 64 ], mitochondrial enzyme knockdown [ 65 ], or treatment with sterols [ 66 ]. In these studies, the previously mentioned features were associated with a possible programmed cell death such as apoptosis or autophagy [ 67 ].…”

Section: Discussionmentioning

confidence: 71%

Induction of programmed cell death in Trypanosoma cruzi by Lippia alba essential oils and their major and synergistic terpenes (citral, limonene and caryophyllene oxide)

Moreno

Pinto

Stashenko

et al. 2018

BMC Complement Altern Med

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BackgroundChagas Disease caused by Trypanosoma cruzi infection, is one of the most important neglected tropical diseases (NTD), without an effective therapy for the successful parasite eradication or for the blocking of the disease’s progression, in its advanced stages. Due to their low toxicity, wide pharmacologic spectrum, and potential synergies, medicinal plants as Lippia alba, offer a promising reserve of bioactive molecules. The principal goal of this work is to characterize the inhibitory properties and cellular effects of the Citral and Carvone L. alba chemotype essential oils (EOs) and their main bioactive terpenes (and the synergies among them) on T. cruzi forms.MethodsTwelve L. alba EOs, produced under diverse environmental conditions, were extracted by microwave assisted hydrodistillation, and chemically characterized using gas chromatography coupled mass spectrometry. Trypanocidal activity and cytotoxicity were determined for each oil, and their major compounds, on epimastigotes (Epi), trypomastigotes (Tryp), amastigotes (Amas), and Vero cells. Pharmacologic interactions were defined by a matrix of combinations among the most trypanocidal terpenes (limonene, carvone; citral and caryophyllene oxide). The treated cell phenotype was assessed by fluorescent and optic microscopy, flow cytometry, and DNA electrophoresis assays.ResultsThe L. alba EOs displayed significant differences in their chemical composition and trypanocidal performance (p = 0.0001). Citral chemotype oils were more trypanocidal than Carvone EOs, with Inhibitory Concentration 50 (IC50) of 14 ± 1.5 μg/mL, 22 ± 1.4 μg/mL and 74 ± 4.4 μg/mL, on Epi, Tryp and Amas, respectively. Limonene exhibited synergistic interaction with citral, caryophyllene oxide and Benznidazole (decreasing by 17 times its IC50) and was the most effective and selective treatment. The cellular analysis suggested that these oils or their bioactive terpenes (citral, caryophyllene oxide and limonene) could be inducing T. cruzi cell death by an apoptotic-like mechanism.ConclusionsEOs extracted from L. alba Citral chemotype demonstrated significant trypanocidal activity on the three forms of T. cruzi studied, and their composition and trypanocidal performance were influenced by production parameters. Citral, caryophyllene oxide, and limonene showed a possible induction of an apoptotic-like phenotype. The best selective anti-T. cruzi activity was achieved by limonene, the effects of which were also synergic with citral, caryophyllene oxide and benznidazole.

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Section: Discussionmentioning

confidence: 71%

Induction of programmed cell death in Trypanosoma cruzi by Lippia alba essential oils and their major and synergistic terpenes (citral, limonene and caryophyllene oxide)

Moreno

Pinto

Stashenko

et al. 2018

BMC Complement Altern Med

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“…The cytosolic TrpRS isoform is not capable of charging this modified tRNA Trp [29]. The essentiality of the separate mitochondrial form has been confirmed by RNA interference [33]. Neither isoform is capable of charging E. coli tRNA Trp [29].…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of three protozoan homologs of tryptophanyl-tRNA synthetase

Merritt¹,

Arakaki²,

Gillespie³

et al. 2011

Molecular and Biochemical Parasitology

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Tryptophanyl-tRNA synthetase (TrpRS) is an essential enzyme that is recognizably conserved across all forms of life. It is responsible for activating and attaching tryptophan to a cognate tRNATrp molecule for use in protein synthesis. In some eukaryotes this original core function has been supplemented or modified through the addition of extra domains or the expression of variant TrpRS isoforms. The three TrpRS structures from pathogenic protozoa described here represent three illustrations of this malleability in eukaryotes. The Cryptosporidium parvum genome contains a single TrpRS gene, which codes for an N-terminal domain of uncertain function in addition to the conserved core TrpRS domains. Sequence analysis indicates that this extra domain, conserved among several apicomplexans, is related to the editing domain of some AlaRS and ThrRS. The C. parvum enzyme remains fully active in charging tRNATrp after truncation of this extra domain. The crystal structure of the active, truncated enzyme is presented here at 2.4 Å resolution. The Trypanosoma brucei genome contains separate cytosolic and mitochondrial isoforms of TrpRS that have diverged in their respective tRNA recognition domains. The crystal structure of the T. brucei cytosolic isoform is presented here at 2.8 Å resolution. The Entamoeba histolytica genome contains three sequences that appear to be TrpRS homologs. However one of these, whose structure is presented here at 3.0 Å resolution, has lost the active site motifs characteristic of the Class I aminoacyl-tRNA synthetase catalytic domain while retaining the conserved features of a fully formed tRNATrp recognition domain. The biological function of this variant E. histolytica TrpRS remains unknown, but, on the basis of a completely conserved tRNA recognition region and evidence for ATP but not tryptophan binding, it is tempting to speculate that it may perform an editing function. Together with a previously reported structure of an unusual TrpRS from Giardia, these protozoan structures broaden our perspective on the extent of structural variation found in eukaryotic TrpRS homologs.

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“…brucei TrpRS-1 and -2 isoforms led to rapid decrease in cell growth and finally complete growth arrest. However, TrpRS-2 has been indicated as a better target because of its lesser sequence identity with that of the human counterpart and its ability to aminoacylate both types of tRNA. , Furthermore, the similarity in the catalytic domains of Tb TrpRS-1 and the cytosolic human TrpRS has been proved with the crystal structure of Tb TrpRS-1 . Inhibitors specifically targeting apicomplexans are available in the database that can be further investigated for their potency in the inhibition of trypanosomatid TrpRSs .…”

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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Effects of Trypanosoma brucei tryptophanyl-tRNA synthetases silencing by RNA interference

Cited by 4 publications

References 10 publications

Induction of programmed cell death in Trypanosoma cruzi by Lippia alba essential oils and their major and synergistic terpenes (citral, limonene and caryophyllene oxide)

Induction of programmed cell death in Trypanosoma cruzi by Lippia alba essential oils and their major and synergistic terpenes (citral, limonene and caryophyllene oxide)

Crystal structures of three protozoan homologs of tryptophanyl-tRNA synthetase

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

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