Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery

McCarty, Sara E.; Schellenberger, Amanda N.; Goodwin, Douglas C.; Fuanta, René; Tekwani, Babu L.; Calderón, Ángela I.

doi:10.3390/molecules200611459

Cited by 18 publications

(6 citation statements)

References 48 publications

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“…The thioredoxin network in particular has been implied to have a role in many cellular processes related to cancer and other forms of disease [ 5 ]. It also constitutes a drug target in several pathogens, including Plasmodium falciparum , the causative agent of malaria [ 6 ], and Entamoeba histolytica , the causative agent of amebiasis [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

An unusual thioredoxin system in the facultative parasite Acanthamoeba castellanii

Leitsch

Mbouaka

Köhsler

et al. 2021

Cell. Mol. Life Sci.

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The free-living amoeba Acanthamoeba castellanii occurs worldwide in soil and water and feeds on bacteria and other microorganisms. It is, however, also a facultative parasite and can cause serious infections in humans. The annotated genome of A. castellanii (strain Neff) suggests the presence of two different thioredoxin reductases (TrxR), of which one is of the small bacterial type and the other of the large vertebrate type. This combination is highly unusual. Similar to vertebrate TrxRases, the gene coding for the large TrxR in A. castellanii contains a UGA stop codon at the C-terminal active site, suggesting the presence of selenocysteine. We characterized the thioredoxin system in A. castellanii in conjunction with glutathione reductase (GR), to obtain a more complete understanding of the redox system in A. castellanii and the roles of its components in the response to oxidative stress. Both TrxRases localize to the cytoplasm, whereas GR localizes to the cytoplasm and the large organelle fraction. We could only identify one thioredoxin (Trx-1) to be indeed reduced by one of the TrxRases, i.e., by the small TrxR. This thioredoxin, in turn, could reduce one of the two peroxiredoxins tested and also methionine sulfoxide reductase A (MsrA). Upon exposure to hydrogen peroxide and diamide, only the small TrxR was upregulated in expression at the mRNA and protein levels, but not the large TrxR. Our results show that the small TrxR is involved in the A. castellanii’s response to oxidative stress. The role of the large TrxR, however, remains elusive.

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Section: Introductionmentioning

confidence: 99%

An unusual thioredoxin system in the facultative parasite Acanthamoeba castellanii

Leitsch

Mbouaka

Köhsler

et al. 2021

Cell. Mol. Life Sci.

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“…The enzymes associated with the antioxidant system play essential roles during parasite survival and infection (18)(19)(20)(21)(22). Peroxiredoxin (Prx) inhibitors inhibit the growth of Plasmodium falciparum and increase parasite sensitivity to chloroquine (23), and inhibition of TR in Schistosoma mansoni and P. falciparum can effectively kill these parasites (18,24). T. gondii is sensitive to oxidative stress, with Prx capable of counteracting the toxic effect of H 2 O 2 on tachyzoites (25).…”

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confidence: 99%

Thioredoxin reductase fromToxoplasma gondii: an essential virulence effector with antioxidant function

et al. 2017

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Thioredoxin reductase (TR) can help pathogens resist oxidative-burst injury from host immune cells by maintaining a thioredoxin-reduction state during NADPH consumption. TR is a necessary virulence factor that enables the persistent infection of some parasites. We performed bioinformatics analyses and biochemical assays to characterize the activity, subcellular localization, and genetic ablation of Toxoplasma gondii TR (TgTR), to shed light on its biologic function. We expressed the TgTR protein with an Escherichia coli expression system and analyzed its enzyme activity, reporting a K m for the recombinant TgTR of 11.47-15.57 mM, using NADPH as a substrate, and 130.48-151.09 mM with dithio-bis-nitrobenzoic acid as a substrate. The TgTR sequence shared homology with that of TR, but lacked a selenocysteine residue in the C-terminal region and was thought to contain 2 flavin adenine dinucleotide (FAD) domains and 1 NADPH domain. In addition, immunoelectron microscopy results showed that TgTR was widely dispersed in the cytoplasm, and we observed that parasite antioxidant capacity, invasion efficiency, and proliferation were decreased in TR-knockout (TR-KO) strains in vitro, although this strain still stimulated the release of reactive oxygen species release in mouse macrophages while being more sensitive to H 2 O 2 toxicity in vitro. Furthermore, our in vivo results revealed that the survival time of mice infected with the TR-KO strain was significantly prolonged relative to that of mice infected with the wild-type strain. These results suggest that TgTR plays an important role in resistance to oxidative damage and can be considered a virulence factor associated with T. gondii

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“…Large NTRs, having multiple CxxxxC motifs have been identified in other Apicomplexa ( Plasmodium falciparum, Toxoplasma gondii, Cryptosporidium spp., and Theilera spp .) (McCarty et al, 2015). In fact, the C-terminal CGGGKC sequence is identical to that of Plasmodium falciparum Large NTR (Hirt et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

Brevetoxin (PbTx-2) influences the redox status and NPQ of Karenia brevis by way of thioredoxin reductase

et al. 2018

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The Florida red tide dinoflagellate, Karenia brevis, is the major harmful algal bloom dinoflagellate of the Gulf of Mexico and plays a destructive role in the region. Blooms of K. brevis can produce brevetoxins: ladder-shaped polyether (LSP) compounds, which can lead to adverse human health effects, such as reduced respiratory function through inhalation exposure, or neurotoxic shellfish poisoning through consumption of contaminated shellfish. The endogenous role of the brevetoxins remains uncertain. Recent work has shown that some forms of NADPH dependent thioredoxin reductase (NTR) are inhibited by brevetoxin-2 (PbTx-2). The study presented herein reveals that high toxin and low toxin K. brevis, which have a ten-fold difference in toxin content, also show a significant difference in their ability, not only to produce brevetoxin, but also in their cellular redox status and distribution of xanthophyll cycle pigments. These differences are likely due to the inhibition of NTR by brevetoxin. The work could shed light on the physiological role that brevetoxin fills for K. brevis.

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Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery

Cited by 18 publications

References 48 publications

An unusual thioredoxin system in the facultative parasite Acanthamoeba castellanii

An unusual thioredoxin system in the facultative parasite Acanthamoeba castellanii

Thioredoxin reductase fromToxoplasma gondii: an essential virulence effector with antioxidant function

Brevetoxin (PbTx-2) influences the redox status and NPQ of Karenia brevis by way of thioredoxin reductase

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