Typical 2-Cys peroxiredoxins in human parasites: Several physiological roles for a potential chemotherapy target

doi:10.1016/j.molbiopara.2016.03.005

Molecular and Biochemical Parasitology

Volume 206, Issues 1–2, March–April 2016, Pages 2-12

This paper is dedicated to our beloved colleague Prof. Donatella Barra, deceased 28 September 2014.

https://doi.org/10.1016/j.molbiopara.2016.03.005 Get rights and content

Highlights

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Typical 2-Cys peroxiredoxins play several functions in eukarya.
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In parasites peroxidase and holdase activities of Prx1 family are correlated with virulence.
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The possibility to inhibit one function over the others is a foreseeable task.
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Due to active site conservation in Prx1 family, synthesis of specific inhibitors is challenging.

Abstract

Peroxiredoxins (Prxs) are ubiquitary proteins able to play multiple physiological roles, that include thiol-dependent peroxidase, chaperone holdase, sensor of H₂O₂, regulator of H₂O₂-dependent signal cascades, and modulator of the immune response. Prxs have been found in a great number of human pathogens, both eukaryotes and prokaryotes. Gene knock-out studies demonstrated that Prxs are essential for the survival and virulence of at least some of the pathogens tested, making these proteins potential drug targets. However, the multiplicity of roles played by Prxs constitutes an unexpected obstacle to drug development. Indeed, selective inhibitors of some of the functions of Prxs are known (namely of the peroxidase and holdase functions) and are here reported. However, it is often unclear which function is the most relevant in each pathogen, hence which one is most desirable to inhibit. Indeed there are evidences that the main physiological role of Prxs may not be the same in different parasites. We here review which functions of Prxs have been demonstrated to be relevant in different human parasites, finding that the peroxidase and chaperone activities figure prominently, whereas other known functions of Prxs have rarely, if ever, been observed in parasites, or have largely escaped detection thus far.

Graphical abstract

Section snippets

Introduction: peroxiredoxin and human pathogens

Peroxiredoxins (Prxs) are ubiquitary enzymes with thiol-dependent peroxidase activity [1], [2]. In some cell types that are exposed to oxidative damage, they can attain very high concentration, such as in the human erythrocytes, where Prx II (formerly called calpromotin or torin) is the third most abundant protein and its concentration is approximately 6 mg/mL [3], [4]. Besides their peroxidase activity, Prxs can play other roles in the cell: they have been demonstrated to act as peroxynitrite

Structure and classification of Prxs

Prxs from eukaryotes were classified into the three classes of typical and atypical 2-Cys Prxs and 1-Cys Prxs by Wood et al. [40], based both on the different mechanism of action in peroxide reduction (the earliest recognized biological activity) and on their localization within the cell. This classification was later refined by Soito et al. [41], who identified six subfamilies (Prx1, Prx6, Prx5, PrxQ, Tpx and AhpE) two of which (AhpE and Tpx) exclusively present in prokaryotes [42].

Typical

The functions of Prxs

As described in the preceding sections, Prxs may play a bewildering array of apparently unrelated biochemical roles, not all of which have been confirmed in parasites. However some of these appear to be so general and widespread to suggest that they may be discovered also in parasites (notably in metazoans), thus we decided to include them in this summary.

Parasites Prxs: which activity is more crucial to virulence?

It has been widely shown that Prxs are ubiquitary in human pathogens, notably in parasites, and that they are virulence factors, as documented by the following examples. Reduction of Prx expression by genetic methods, such as gene knock-out (KO) or RNA interference (RNAi), has been demonstrated to be lethal for parasites both in vivo and in vitro. Strains of P. falciparum in which the Prx1a gene was knocked out exhibited hypersensitivity to heat stress and to oxidative stress induced by

Conclusions

Prxs are ubiquitous and play many physiological roles; they might constitute interesting pharmacological potential targets for several pathological conditions, that include some important parasitic diseases, like malaria, trypanosomiasis, leishmaniasis and schistosomiasis. In this review we collected information on: (i) the main physiological roles of Prxs in parasites; (ii) the structural features that are critical to these roles; and (iii) the few available inhibitors capable to target either

Acknowledgements

The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (grant agreement N°283570), and from Sapienza University grants 2013 and 2014 to A.B. and A.E.M.

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For example, parasites are subjected to reactive oxygen species (ROS) generated from their own metabolism and to the oxidative stress imposed by the host's immune response, making the antioxidant system indispensable for worm survival. Proteins implicated in the ROS detoxification mechanisms are promising targets in drug discovery projects aimed at eliminating diseases in general [14–20]. Redox balance in most organisms is controlled by the action of two parallel systems, one based on glutathione (GSH), and the other based on isoforms of thioredoxin (Trx), both of which play central roles in regulating redox homeostasis and are involved in crucial physiological functions such as DNA synthesis [21–23].
Enzymes in the thiol redox systems of microbial pathogens are promising targets for drug development. In this study we characterized the thioredoxin reductase (TrxR) selenoproteins from Brugia malayi and Onchocerca volvulus, filarial nematode parasites and causative agents of lymphatic filariasis and onchocerciasis, respectively. The two filarial enzymes showed similar turnover numbers and affinities for different thioredoxin (Trx) proteins, but with a clear preference for the autologous Trx. Human TrxR1 (hTrxR1) had a high and similar specific activity versus the human and filarial Trxs, suggesting that, in vivo, hTrxR1 could possibly be the reducing agent of parasite Trxs once they are released into the host. Both filarial TrxRs were efficiently inhibited by auranofin and by a recently described inhibitor of human TrxR1 (TRi-1), but not as efficiently by the alternative compound TRi-2. The enzyme from B. malayi was structurally characterized also in complex with NADPH and auranofin, producing the first crystallographic structure of a nematode TrxR. The protein represents an unusual fusion of a mammalian-type TrxR protein architecture with an N-terminal glutaredoxin-like (Grx) domain lacking typical Grx motifs. Unlike thioredoxin glutathione reductases (TGRs) found in platyhelminths and mammals, which are also Grx–TrxR domain fusion proteins, the TrxRs from the filarial nematodes lacked glutathione disulfide reductase and Grx activities. The structural determinations revealed that the Grx domain of TrxR from B. malayi contains a cysteine (C22), conserved in TrxRs from clade IIIc nematodes, that directly interacts with the C-terminal cysteine-selenocysteine motif of the homo-dimeric subunit. Interestingly, despite this finding we found that altering C22 by mutation to serine did not affect enzyme catalysis. Thus, although the function of the Grx domain in these filarial TrxRs remains to be determined, the results obtained provide insights on key properties of this important family of selenoprotein flavoenzymes that are potential drug targets for treatment of filariasis.
Taking Advantage of the Morpheein Behavior of Peroxiredoxin in Bionanotechnology
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Morpheeins are proteins that reversibly assemble into different oligomers, whose architectures are governed by conformational changes of the subunits. This property could be utilized in bionanotechnology where the building of nanometric and new high-ordered structures is required. By capitalizing on the adaptability of morpheeins to create patterned structures and exploiting their inborn affinity toward inorganic and living matter, “bottom-up” creation of nanostructures could be achieved using a single protein building block, which may be useful as such or as scaffolds for more complex materials. Peroxiredoxins represent the paradigm of a morpheein that can be applied to bionanotechnology. This review describes the structural and functional transitions that peroxiredoxins undergo to form high-order oligomers, e.g., rings, tubes, particles, and catenanes, and reports on the chemical and genetic engineering approaches to employ them in the generation of responsive nanostructures and nanodevices. The usefulness of the morpheeins’ behavior is emphasized, supporting their use in future applications.
Intestinal protozoa and helminths in ulcerative colitis and the influence of anti-parasitic therapy on the course of the disease
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Reinfection of a second batch of mice with an ST7 isolate obtained from faecal culture demonstrated similar histopathological findings and tissue damage, proving Koch's postulates for this parasite [23]. Peroxiredoxins are proteins that are essential for the survival and virulence of pathogenic eukaryotes and prokaryotes [24]. Peroxiredoxins (Prx1a and Prx1m) were identified in Blastocystis hominis [25].
The aim of this study is to determine the prevalence of intestinal helminths and protozoa in patients with ulcerative colitis (UC) and to estimate the influence of the anti-parasitic therapy on the course of the disease.
The study was conducted at the Research Institute of Epidemiology, Microbiology and Infectious Diseases and Coloproctology Department of the Republic Clinical Hospital №1 of the Ministry of Health of the Republic of Uzbekistan. One hundred UC patients and 200 healthy individuals were examined by triple coproscopy. Additionally, 20, 25 and 22 UC patients with Blastocystis infection were treated with nitazoxanide (1.0 g/day), mesalazine (1.5-2 g/day) or a combination of nitazoxanide (1.0 g/day) and mesalazine (≥1.5-2 g/day) for 14 consecutive days, respectively. Parasitological, clinical and endoscopic examinations were conducted before therapy, immediately after and 6 and 12 weeks after therapy completion.
The overall prevalence of helminths in UC patients and control individuals was not significantly different: 14±3.4% and 8.5±1.9%, respectively (OR: 1.7524; 95% CI: 0.8258 to 3.7186; P=0.1). Giardia lamblia was the most prevalent parasite in both groups, but the difference compared to the control was insignificant (OR: 0.4565; 95% CI: 0.2020 to 1.0318; P=0.05). A significantly higher prevalence of Blastocystis sp., Chilomastix mesnili and Iodamoeba butschlii in UC patients compared to control individuals was found (P<0.0005): 65.0%, 14.0% and 22.0%, respectively. During all follow-up periods, the clinical response and clinical remission were not statistically different between the groups (P>0.05). Mucosal healing immediately and 6 weeks after therapy with a combination of nitazoxanide with mesalazine was significantly better than with a monotherapy of nitazoxanide, respectively (P<0.05). UC patients treated with a combination of nitazoxanide with mesalazine showed better mucosal healing than in patients treated with a monotherapy of mesalazine (P>0.05).
Diagnosis of Blastocystis sp. should be introduced in the complex examination of UC patients. Further clinical studies are necessary for assessment of the efficiency of anti-Blastocystis therapy in UC patients.
Oligomerization dynamics and functionality of Trypanosoma cruzi cytosolic tryparedoxin peroxidase as peroxidase and molecular chaperone
2019, Biochimica et Biophysica Acta - General Subjects
Citation Excerpt :
c-TXNPxC173S was shown to be the most sensitive to overoxidation, which is in accordance with the role of this missing residue as CR in the formation of a disulfide bond with CP. Several previous studies have indicated the essential role of trypanothione-dependent antioxidant mechanisms of trypanosomatids [3,39] as key virulence factors which would enable these parasites to respond to the oxidizing environment they confront during their infective cycle. Therefore, the components of this system are potentially attractive targets for the design of chemotherapeutic agents.
Trypanosoma cruzi cytosolic tryparedoxin peroxidase (c-TXNPx) is a 2-Cys peroxiredoxin that plays an important role in coping with host cell oxidative response during the infection process, for which it has been described as a virulence factor.
Four residues corresponding to c-TXNPx catalytic and solvent-exposed cysteines were individually mutated to serine by site-specific mutagenesis. Susceptibility to redox treatments and oligomeric dynamics were investigated by western-blot and gel filtration chromatography. Chaperone and peroxidase activities were determined.
In this study we demonstrated that c-TXNPx exists as different oligomeric forms, from decameric to high molecular mass aggregates. Moreover, c-TXNPx functions as a dual-function protein acting both as a peroxidase and as a molecular chaperone. Its chaperone function was shown to be independent of the presence of catalytic cysteines, even in the reduced and decameric forms, although it is enhanced when the protein is overoxidized leading to the formation of high molecular mass aggregates.
c-TXNPx has chaperone activity which does not depend on the redox state. c-TXNPx does not undergo the dimer-decamer transition in the oxidized state described for other peroxiredoxins. Overoxidized c-TXNPx exists as different oligomeric forms from decamer to high molecular mass aggregates which are in a very slow dynamic equilibrium. The non-catalytic C57 residue may have a role in the maintenance of the decameric form, but seems not to have an alternative C_P and C_R role.
This study provides novel insights into some key aspects of the oligomerization dynamics and function of c-TXNPx.
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This is indeed surprising as other trichomonadid parasites, including T. vaginalis, do not have this enzyme. Instead, H2O2 is removed mostly by peroxiredoxins via a cysteinyl-dependent mechanism through reduction to water [21]. Likewise, alkyl peroxides are reduced to water and the corresponding alcohol.
The microaerophilic parasites Entamoeba histolytica, Trichomonas vaginalis, and Giardia lamblia jointly cause hundreds of millions of infections in humans every year. Other microaerophilic parasites such as Tritrichomonas foetus and Spironucleus spp. pose a relevant health problem in veterinary medicine. Unfortunately, vaccines against these pathogens are unavailable, but their microaerophilic lifestyle opens opportunities for specifically developed chemotherapeutics. In particular, their high sensitivity towards oxygen can be exploited by targeting redox enzymes. This review focusses on the redox pathways of microaerophilic parasites and on drugs, either already in use or currently in the state of development, which target these pathways.
Calcium and magnesium ions modulate the oligomeric state and function of mitochondrial 2-Cys peroxiredoxins in Leishmania parasites
2017, Journal of Biological Chemistry
Citation Excerpt :
Furthermore, we have demonstrated that the decameric structure, independently of its redox state, is both necessary and sufficient for the protective effect of Prx1m against heat stress in Leishmania, a vital attribute for the establishment of a successful infection in the mammalian host (2, 3). This finding implies that the search for compounds that prevent Prx1m decamerization represents the best strategy for inhibiting the crucial chaperone function of this attractive therapeutic target (36). Zhao et al. (37) already have identified chaperone inhibitors for the human Prx I, demonstrating the feasibility of such an approach.
Leishmania parasites have evolved a number of strategies to cope with the harsh environmental changes during mammalian infection. One of these mechanisms involves the functional gain that allows mitochondrial 2-Cys peroxiredoxins to act as molecular chaperones when forming decamers. This function is critical for parasite infectivity in mammals, and its activation has been considered to be controlled exclusively by the enzyme redox state under physiological conditions. Herein, we have revealed that magnesium and calcium ions play a major role in modulating the ability of these enzymes to act as molecular chaperones, surpassing the redox effect. These ions are directly involved in mitochondrial metabolism and participate in a novel mechanism to stabilize the decameric form of 2-Cys peroxiredoxins in Leishmania mitochondria. Moreover, we have demonstrated that a constitutively dimeric Prx1m mutant impairs the survival of Leishmania under heat stress, supporting the central role of the chaperone function of Prx1m for Leishmania parasites during the transition from insect to mammalian hosts.

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¹: These authors contributed equally to this work.

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Typical 2-Cys peroxiredoxins in human parasites: Several physiological roles for a potential chemotherapy target

Highlights

Abstract

Graphical abstract

Section snippets

Introduction: peroxiredoxin and human pathogens

Structure and classification of Prxs

The functions of Prxs

Parasites Prxs: which activity is more crucial to virulence?

Conclusions

Acknowledgements

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