Cloning of Plasmodium falciparum protein disulfide isomerase homologue by affinity purification using the antiplasmodial inhibitor 1,4‐bis{3‐[N‐(cyclohexyl methyl)amino]propyl}piperazine 1

Florent, Isabelle; Mouray, Elisabeth; Ali, Fouad Dali; Drobecq, Hervé; Girault, Sophie; Schrével, Joseph; Sergheraert, Christian; Grellier, Philippe

doi:10.1016/s0014-5793(00)02170-0

Cited by 23 publications

(13 citation statements)

References 43 publications

(71 reference statements)

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“…PfGR is inhibited by S-nitrosoglutathione, which induces oxidation of one of the catalytically essential cysteines (43). Protein disulfide isomerases are members of the thiol:disulfide oxidoreductase superfamily (44). Two Cys residues form part of the Trx-like catalytic sites (-CGHC-), and are essential for activity.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Heme-interacting Proteins in the Malaria Parasite, Plasmodium falciparum

Campanale

Nickel²,

Daubenberger

et al. 2003

Journal of Biological Chemistry

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The degradation of hemoglobin by the malaria parasite, Plasmodium falciparum, produces free ferriprotoporphyrin IX (FP) as a toxic by-product. In the presence of FP-binding drugs such as chloroquine, FP detoxification is inhibited, and the build-up of free FP is thought to be a key mechanism in parasite killing. In an effort to identify parasite proteins that might interact preferentially with FP, we have used a mass spectrometry approach. Proteins that bind to FP immobilized on agarose include P. falciparum glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH), P. falciparum glutathione reductase (PfGR), and P. falciparum protein disulfide isomerase. To examine the potential consequences of FP binding, we have examined the ability of FP to inhibit the activities of GAPDH and GR from P. falciparum and other sources. FP inhibits the enzymic activity of Pf-GAPDH with a K i value of 0.2 M, whereas red blood cell GAPDH is much less sensitive. By contrast, PfGR is more resistant to FP inhibition (K i > 25 M) than its human counterpart. We also examined the ability of FP to inhibit the activities of the additional antioxidant enzymes, P. falciparum thioredoxin reductase, which exhibits a K i value of 1 M, and P. falciparum glutaredoxin, which shows more moderate sensitivity to FP. The exquisite sensitivity of PfGAPDH to FP may indicate that the glycolytic pathway of the parasite is particularly susceptible to modulation by FP stress. Inhibition of this pathway may drive flux through the pentose phosphate pathway ensuring sufficient production of reducing equivalents to counteract the oxidative stress induced by FP build-up.

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Heme-interacting Proteins in the Malaria Parasite, Plasmodium falciparum

Campanale

Nickel²,

Daubenberger

et al. 2003

Journal of Biological Chemistry

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“…T. gondii protein disulfide isomerase (PDI) is one of the new candidate antigens identified among soluble tachyzoite antigens using rabbit anti- T. gondii serum by two-dimensional gel electrophoresis and proteomics analyses [11]. PDIs not only highly expressed in T. gondii and Neospora caninum [12], [13], but are also found in virtually all eukaryotic cells in several protozoan parasites, such as Cryptosporidium parvum [14], Plasmodium falciparum [15], Leishmania major [16], and Leishmania donovani [17]. PDIs exhibit oxidoreductase, isomerase, and chaperone activities, ensuring the proper folding and conformation of the proteins by catalysing the formation or oxidation of disulfide bridges [18], [19].…”

Section: Introductionmentioning

confidence: 99%

Toxoplasma gondii Protein Disulfide Isomerase (TgPDI) Is a Novel Vaccine Candidate against Toxoplasmosis

Wang

Yin

et al. 2013

PLoS ONE

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Toxoplasma gondii is a ubiquitous protozoan parasite that can infect all warm-blooded animals, including both mammals and birds. Protein disulfide isomerase (PDI) localises to the surface of T. gondii tachyzoites and modulates the interactions between parasite and host cells. In this study, the protective efficacy of recombinant T. gondii PDI (rTgPDI) as a vaccine candidate against T. gondii infection in BALB/c mice was evaluated. rTgPDI was expressed and purified from Escherichia coli. Five groups of animals (10 animals/group) were immunised with 10, 20, 30, 40 μg of rTgPDI per mouse or with PBS as a control group. All immunisations were performed via the nasal route at 1, 14 and 21 days. Two weeks after the last immunisation, the immune responses were evaluated by lymphoproliferative assays and by cytokine and antibody measurements. The immunised mice were challenged with tachyzoites of the virulent T. gondii RH strain on the 14th day after the last immunisation. Following the challenge, the tachyzoite loads in tissues were assessed, and animal survival time was recorded. Our results showed that the group immunised with 30 μg rTgPDI showed significantly higher levels of specific antibodies against the recombinant protein, a strong lymphoproliferative response and significantly higher levels of IgG2a, IFN-gamma (IFN-γ), IL-2 and IL-4 production compared with other doses and control groups. While no changes in IL-10 levels were detected. After being challenged with T. gondii tachyzoites, the numbers of tachyzoites in brain and liver tissues from the rTgPDI group were significantly reduced compared with those of the control group, and the survival time of the mice in the rTgPDI group was longer than that of mice in the control group. Our results showed that immunisation with rTgPDI elicited a protective immune reaction and suggested that rTgPDI might represent a promising vaccine candidate for combating toxoplasmosis.

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“…In order to investigate the localization of OtuLi in promastigotes, a mitochondrion probe, or the Protein Disulfide-Isomerase (PDI) antibody (Florent et al, 2000) were employed to label mitochondrion and endoplasmic reticulum, respectively. OtuLi is presented in small vesicles along the cytoplasm of the cell, although an intense fluorescence can be observed near kinetoplast.…”

Section: Resultsmentioning

confidence: 99%

Revealing a Novel Otubain-Like Enzyme from Leishmania infantum with Deubiquitinating Activity toward K48-Linked Substrate

et al. 2017

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Deubiquitinating enzymes (DUBs) play an important role in regulating a variety of eukaryotic processes. In this context, exploring the role of deubiquitination in Leishmania infantum could be a promising alternative to search new therapeutic targets for leishmaniasis. Here we present the first characterization of a DUB from L. infantum, otubain (OtuLi), and its localization within parasite. The recombinant OtuLi (rOtuLi) showed improved activity on lysine 48 (K48)-linked over K63-linked tetra-ubiquitin (Ub) and site-directed mutations on amino acids close to the catalytic site (F82) or involved in Ub interaction (L265 and F182) caused structural changes as shown by molecular dynamics, resulting in a reduction or loss of enzyme activity, respectively. Furthermore, rOtuLi stimulates lipid droplet biogenesis (an inflammatory marker) and induces IL-6 and TNF-α secretion in peritoneal macrophages, both proinflammatory cytokines. Our findings suggest that OtuLi is a cytoplasmic enzyme with K48-linked substrate specificity that could play a part in proinflammatory response in stimulated murine macrophages.

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Cloning of Plasmodium falciparum protein disulfide isomerase homologue by affinity purification using the antiplasmodial inhibitor 1,4‐bis{3‐[N‐(cyclohexyl methyl)amino]propyl}piperazine ¹

Cited by 23 publications

References 43 publications

Identification and Characterization of Heme-interacting Proteins in the Malaria Parasite, Plasmodium falciparum

Identification and Characterization of Heme-interacting Proteins in the Malaria Parasite, Plasmodium falciparum

Toxoplasma gondii Protein Disulfide Isomerase (TgPDI) Is a Novel Vaccine Candidate against Toxoplasmosis

Revealing a Novel Otubain-Like Enzyme from Leishmania infantum with Deubiquitinating Activity toward K48-Linked Substrate

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