Leishmania donovani Encodes a Functional Selenocysteinyl-tRNA Synthase

Manhas, Reetika; Gowri, Vijayendran; Madhubala, Rentala

doi:10.1074/jbc.m115.695007

Cited by 13 publications

(11 citation statements)

References 44 publications

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“…Selenium derivatives have been recognized by antioxidant, cancer preventing, and antiviral activities. Selenoproteins interfere with kinetoplastid biochemistry and have antiparasite activities (6). Similarly, increased selenium concentration in plasma has been proposed as a new defensive strategy against Leishmania infection (7).…”

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confidence: 99%

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

Díaz

Lucio

Moreno

et al. 2019

Antimicrob Agents Chemother

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A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC 50 ) values lower than that for the reference drug miltefosine (EC 50 , 2.84 M). In addition, the derivatives 9, 11, 42, and 47, with EC 50 between 1.1 and 1.95 M, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC 50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.

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confidence: 99%

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

Díaz

Lucio

Moreno

et al. 2019

Antimicrob Agents Chemother

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“…brucei viability [ 11 ]. SEPSECS knockout experiments further established that there is no significant contribution of selenoproteins to redox homeostasis in trypanosomatids [ 11 , 13 , 27 , 28 ]. Indeed, we further show that Tb SELENOT knockdown does not significantly impact PCF and BSF T .…”

Section: Discussionmentioning

confidence: 99%

“…cruzi [ 12 ] and L . donovani [ 13 ]. Selenocysteine biosynthesis and incorporation into selenoproteins require an intricate molecular machinery that is present, but not ubiquitous, in all domains of life [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…This result also seems to be valid for other trypanosomatids, since L . donovani SEPSECS null mutant promastigote ( Ld SEPSECS) cell lines show normal growth even upon oxidative stress, and during macrophage infection [ 13 ]. On the other hand, Tb SEPHS2 RNAi PCF and BSF T .…”

Section: Introductionmentioning

confidence: 99%

“…brucei PCF [ 27 ] or the counterpart L . donovani amastigote [ 13 ]. SELENOTryp (SelTryp) is a novel selenoprotein exclusive to trypanosomatids that contains a conserved C-terminal redox motif, often found in selenoproteins that carry out redox reactions through the reversible formation of a selenenylsulfide bond [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Trypanosomatid selenophosphate synthetase structure, function and interaction with selenocysteine lyase

Silva

Faim

et al. 2020

PLoS Negl Trop Dis

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Eukaryotes from the Excavata superphylum have been used as models to study the evolution of cellular molecular processes. Strikingly, human parasites of the Trypanosomatidae family ( T . brucei , T . cruzi and L . major ) conserve the complex machinery responsible for selenocysteine biosynthesis and incorporation in selenoproteins (SELENOK/SelK, SELENOT/SelT and SELENOTryp/SelTryp), although these proteins do not seem to be essential for parasite viability under laboratory controlled conditions. Selenophosphate synthetase (SEPHS/SPS) plays an indispensable role in selenium metabolism, being responsible for catalyzing the formation of selenophosphate, the biological selenium donor for selenocysteine synthesis. We solved the crystal structure of the L . major selenophosphate synthetase and confirmed that its dimeric organization is functionally important throughout the domains of life. We also demonstrated its interaction with selenocysteine lyase (SCLY) and showed that it is not present in other stable assemblies involved in the selenocysteine pathway, namely the phosphoseryl-tRNA Sec kinase (PSTK)-Sec-tRNA Sec synthase (SEPSECS) complex and the tRNA Sec -specific elongation factor (eEFSec) complex. Endoplasmic reticulum stress with dithiothreitol (DTT) or tunicamycin upon selenophosphate synthetase ablation in procyclic T . brucei cells led to a growth defect. On the other hand, only DTT presented a negative effect in bloodstream T . brucei expressing selenophosphate synthetase-RNAi. Furthermore, selenoprotein T (SELENOT) was dispensable for both forms of the parasite. Together, our data suggest a role for the T . brucei selenophosphate synthetase in the regulation of the parasite’s ER stress response.

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Selenium and protozoan parasitic infections: selenocompounds and selenoproteins potential

et al. 2022

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The current drug treatments against protozoan parasitic diseases including Chagas, malaria, leishmaniasis, and toxoplasmosis represent good examples of drug resistance mechanisms and have shown diverse side effects. Therefore, the identification of novel therapeutic strategies and drug compounds against such life-threatening diseases is urgent. According to the successful usage of selenium (Se) compounds-based therapy against some diseases, this therapeutic strategy has been recently further underlined against these parasitic diseases by targeting different parasite´s essential pathways. On the other hand, due to the important functions played by parasite selenoproteins in their biology (such as modulating the host immune response), they can be also considered as a novel therapeutic strategy by designing specific inhibitors against these important proteins. In addition, the immunomodulatory potentiality of these compounds to trigger T helper type 1 (Th1) cells and cytokinemediated immune response for the substantial induction of proinflammatory cytokines, thus, Se, selenoproteins, and parasite selenoproteins could be further investigated to find possible vaccine antigens. Herein, we collect and present the results of some studies regarding Se-based therapy against protozoan parasitic diseases and highlight relevant information and some viewpoints that might be insightful to advance toward more effective studies in the future.

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Leishmania donovani Encodes a Functional Selenocysteinyl-tRNA Synthase

Cited by 13 publications

References 44 publications

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

Trypanosomatid selenophosphate synthetase structure, function and interaction with selenocysteine lyase

Selenium and protozoan parasitic infections: selenocompounds and selenoproteins potential

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