Up-regulation of cytosolic tryparedoxin in Amp B resistant isolates of Leishmania donovani and its interaction with cytosolic tryparedoxin peroxidase

Suman, SS; Equbal, Asif; Zaidi, Amir; Ansari, Yousuf; Kp, Singh; Purkait, Bidyut; Gc, Sahoo; Bimal, Sanjiva; Das, Pradeep; Ali, Sajid

doi:10.1016/j.biochi.2015.12.017

Cited by 37 publications

(30 citation statements)

References 82 publications

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“…Over-expression studies of cTXNPx in T. cruzi [25], [26] and L. chagasi [27] resulted in enhanced resistance towards free radical species. Recently, we also reported up-regulation of cTXN at translational level accompanied by enhanced peroxidase activity in Amp B resistant L. donovani clinical isolates [18]. These findings suggest that TryS, TryR, TXN and TXNPx proteins have a pivotal role in drug resistance and redox homeostasis.…”

Section: Introductionmentioning

confidence: 57%

“…Moreover, up-regulation of several proteins of thiol pathway has been implicated in imparting stress tolerance and acquisition of drug resistance by the parasites [18], [20], [40]. To explore a potentially similar mechanism of acquisition of drug resistance by S1-OE parasites, the stress tolerance sensitivity of S1 and S1-OE towards different oxidants were determined by comparing their cell viability at regular intervals of 3 h after treatment with increasing concentrations of oxidants.…”

Section: Resultsmentioning

confidence: 99%

“…The major metabolic proteins which play pleiotropic role in redox homeostasis and drug resistance are the T(SH) 2 -dependent peroxidase, SOD, APx and GST [18], [40], [65]. As reported, T(SH) 2 -dependent peroxidase and tryparedoxin couple constitutes efficient peroxide detoxification machinery for the parasites; aptly associated with drug resistance [13], [18], [66]. SODs are metalloproteins which detoxifies superoxide anions (O 2 - ) by converting them to molecular O 2 or H 2 O 2 [67].…”

Section: Discussionmentioning

confidence: 99%

“…T(SH) 2 dependent peroxidase activity assay was carried out as described previously [18], [51]. The rate of oxidation of NADPH was measured for 5 min at 340 nm using a spectrophotometer (U3900, Hitachi, Japan) followed by the addition of H 2 O 2 and cell lysate to the reaction mixture.…”

Section: Methodsmentioning

confidence: 99%

“…Among low molecular mass antioxidants proteins; tryparedoxin (TXN) and tryparedoxin peroxidase (TXNPx) proteins play a pivotal role in the regulation of metabolic reconfiguration against oxidative and nitrosative stress viz. reduction of hydrogen peroxide, hydroperoxides and peroxynitrite [17], [18]. Therefore, combined action of TryS, TryR, TXN and TXNPx helps to alleviate ROS and together they orchestrate redox metabolism of the parasites which is vital for their survival [19].…”

Section: Introductionmentioning

confidence: 99%

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Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating Amphotericin B resistance and survival of Leishmania donovani under oxidative stress

et al. 2017

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Leishmania donovani is the causative organism of the neglected human disease known as visceral leishmaniasis which is often fatal, if left untreated. The cysteine biosynthesis pathway of Leishmania may serve as a potential drug target because it is different from human host and regulates downstream components of redox metabolism of the parasites; essential for their survival, pathogenicity and drug resistance. However, despite the apparent dependency of redox metabolism of cysteine biosynthesis pathway, the role of L. donovani cysteine synthase (LdCS) in drug resistance and redox homeostasis has been unexplored. Herein, we report that over-expression of LdCS in Amphotericin B (Amp B) sensitive strain (S1-OE) modulates resistance towards oxidative stress and drug pressure. We observed that antioxidant enzyme activities were up-regulated in S1-OE parasites and these parasites alleviate intracellular reactive oxygen species (ROS) efficiently by maintaining the reduced thiol pool. In contrast to S1-OE parasites, Amp B sensitive strain (S1) showed higher levels of ROS which was positively correlated with the protein carbonylation levels and negatively correlated with cell viability. Moreover, further investigations showed that LdCS over-expression also augments the ROS-primed induction of LdCS-GFP as well as endogenous LdCS and thiol pathway proteins (LdTryS, LdTryR and LdcTXN) in L. donovani parasites; which probably aids in stress tolerance and drug resistance. In addition, the expression of LdCS was found to be up-regulated in Amp B resistant isolates and during infective stationary stages of growth and consistent with these observations, our ex vivo infectivity studies confirmed that LdCS over-expression enhances the infectivity of L. donovani parasites. Our results reveal a novel crosstalk between LdCS and thiol metabolic pathway proteins and demonstrate the crucial role of LdCS in drug resistance and redox homeostasis of Leishmania.

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Section: Introductionmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating Amphotericin B resistance and survival of Leishmania donovani under oxidative stress

et al. 2017

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Quantitative proteomic analysis to determine differentially expressed proteins in axenic amastigotes of Leishmania tropica and Leishmania major

et al. 2020

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Cutaneous leishmaniasis is commonly caused by Leishmania major and Leishmania tropica. In the present study, the differential expression of proteins was identified in the amastigote‐like forms of L. tropica and L. major in Iranian isolates. Initially, the samples were cultured and identified using PCR‐RFLP technique. The Leishmania isolates were then grown in host‐free (axenic) culture and prepared to amastigote‐like forms, followed by the extraction of their proteins. To identify significant differentially expressed proteins (DEPs) of two types of Leishmania, the label‐free quantitative proteomic technique was used based on sequential window acquisition of all theoretical fragment ion spectra mass spectrometry. A total of 51 up/down‐DEPs (fold change >2 and p‐value <.05) were identified between the axenic amastigote forms of L. major and L. tropica. Of these, 34 and 17 proteins were up‐regulated in L. major and L. tropica, respectively. Several enriched GO terms were identified via biological process analyses for DEPs; furthermore, the metabolic process and translation were disclosed as top category in the up‐regulated proteins of both L. major and L. tropica species. Also, the KEGG analysis revealed carbon metabolism and metabolic pathways term as the top pathways in the proteins up‐regulated in L. major and L. tropica, respectively. Taken together, the numerous novel DEPs identified between the studied species could help fully understand the molecular mechanisms of pathogenesis and provide potential drug targets and vaccine candidates.

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Global distribution of treatment resistance gene markers for leishmaniasis

Salari

Bamorovat

Sharifi

et al. 2022

Clinical Laboratory Analysis

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The protozoan parasites belonging to the genus Leishmania are pathogenic agents of a complex and non-contagious disease, leishmaniasis. 1,2 Different clinical manifestations are present for this tropical disease ranging from benign self-healing cutaneous (CL) and mucocutaneous (MCL) to a deadly visceral (VL) leishmaniasis. 3 The major species to cause CL in the Old World consist of Leishmania major (L. major) and Leishmania tropica (L. tropica). 4 Over 70% of the global CL cases occur in Algeria,

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Up-regulation of cytosolic tryparedoxin in Amp B resistant isolates of Leishmania donovani and its interaction with cytosolic tryparedoxin peroxidase

Cited by 37 publications

References 82 publications

Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating Amphotericin B resistance and survival of Leishmania donovani under oxidative stress

Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating Amphotericin B resistance and survival of Leishmania donovani under oxidative stress

Quantitative proteomic analysis to determine differentially expressed proteins in axenic amastigotes of Leishmania tropica and Leishmania major

Global distribution of treatment resistance gene markers for leishmaniasis

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