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Review
. 2017 Feb 10;22(2):259.
doi: 10.3390/molecules22020259.

The Architecture of Thiol Antioxidant Systems among Invertebrate Parasites

Alberto Guevara-Flores  1 , José de Jesús Martínez-González  1 , Juan Luis Rendón  2 , Irene Patricia Del Arenal  3
Affiliations
Review

The Architecture of Thiol Antioxidant Systems among Invertebrate Parasites

Alberto Guevara-Flores et al. Molecules. .

Abstract

The use of oxygen as the final electron acceptor in aerobic organisms results in an improvement in the energy metabolism. However, as a byproduct of the aerobic metabolism, reactive oxygen species are produced, leaving to the potential risk of an oxidative stress. To contend with such harmful compounds, living organisms have evolved antioxidant strategies. In this sense, the thiol-dependent antioxidant defense systems play a central role. In all cases, cysteine constitutes the major building block on which such systems are constructed, being present in redox substrates such as glutathione, thioredoxin, and trypanothione, as well as at the catalytic site of a variety of reductases and peroxidases. In some cases, the related selenocysteine was incorporated at selected proteins. In invertebrate parasites, antioxidant systems have evolved in a diversity of both substrates and enzymes, representing a potential area in the design of anti-parasite strategies. The present review focus on the organization of the thiol-based antioxidant systems in invertebrate parasites. Differences between these taxa and its final mammal host is stressed. An understanding of the antioxidant defense mechanisms in this kind of parasites, as well as their interactions with the specific host is crucial in the design of drugs targeting these organisms.

Keywords: antioxidant systems; disulfide reductase; parasites; redox mechanisms; redoxin; thiol; thiol-dependent peroxidase.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Major pathways for ROS production in invertebrate parasites inside its host and the antioxidant defense system. Superoxide anion (O2−) is produced as a metabolic byproduct in both the parasite and its host. To contend with the deleterious effect of its ROS derivatives, a typical antioxidant defense system is present in the parasite. It is constituted by a thiol-dependent peroxidase (X-Px) which transfers electrons from a reduced donor substrate (X-(SH)2) to H2O2. The resulting oxidized form of the substrate [X-(S)2] is then reduced by a specific disulfide reductase.
Figure 2
Figure 2
Diversity of thiol-containing redox substrates in invertebrate parasites. (A) The thiol-containing substrates of low molecular weight cysteine (Cys), glutathione (GSH), trypanothione (T-SH2) and ovothiol (OSH) are shown. Both the reduced and the disulfide form of each compound is shown; (B) Schematic representation of the three-dimensional structure of the thiol-containing substrates of protein nature as thioredoxin (Trx), glutaredoxin (Grx), tryparedoxin (TXN), and Plasmoredoxin (Plrx). Active sites are shown in yellow. For Trx, Grx, and TXN the corresponding PDB file is indicated. The model corresponding to Plrx was constructed from the amino acid sequence data base by using the automatized SWISS-MODEL server (http://swissmodel.expasy.org). Models were drawn with PyMOL.
Figure 3
Figure 3
General catalytic mechanisms for monothiol and dithiol redoxins. (A) General catalytic cycle for the reduction of a protein disulfide by a redoxin. The potential electron donor for the redoxin can be a low molecular weight thiol (LMW-SH) or a high molecular weight thiol (X-protein (SH)2; (B) General catalytic cycle for the deglutathionylation of a protein-glutathione mixed disulfide by either a dithiol or a monothiol glutaredoxin. In this case, GSH is the obligate electron donor.
Figure 4
Figure 4
General catalytic cycles involved in H2O2 reduction by either thiol- or selenol-dependent peroxidases in invertebrate parasites. (A) Sec-dependent Glutathione Peroxidase; (B) Cys-dependent Glutathione Peroxidase; (C) dithiol Glutathione Peroxidase-like from Kinetoplastida. Although structurally similar to GPx, the peroxidase from Kinetoplastida is catalytically similar to the tryparedoxin-dependent peroxiredoxin. X-(SH)2 stand for a dithiol protein from the thioredoxin family (D) dithiol peroxiredoxin.
Figure 5
Figure 5
Mechanisms involved in the overoxidation of the catalytic Sec or Cys in representative enzymes. Both the catalytic and the overoxidative pathways in a Sec-dependent Glutathione Peroxidase (A), and in a Cys-dependent peroxiredoxin (B) are detailed. The different oxidation states for both Sec and Cys are shown. Reversible reactions in the overoxidative pathways are indicated by dotted lines. Abbreviations are as follows: sulfiredoxin (Srx); reduced thiol-dependent substrate (XSH); disulfide form of a thiol-dependent substrate (XSSX).
Figure 6
Figure 6
General catalytic mechanism of disulfide reductase enzymes in invertebrate parasites. In panel (a) a simplified pathway for electron transfer from NADPH to a disulfide substrate is shown. This route is present in enzymes such as glutathione reductase (GR), trypanothione reductase (TryR), and the low-molecular weight thioredoxin reductase (L-TrxR). Panel (b) shows the additional reactions involved in the disulfide reduction followed by the high-molecular weight thioredoxin-reductase (H-TrxR). In panel (c) the additional pathway for electron transfer found in thioredoxin-glutathione reductase (TGR) is shown.
Figure 7
Figure 7
Architecture of the thiol-based antioxidant systems in animals. The organization of the antioxidant redox system present in the phylum Vertebrata (A); and in the parasite representatives of the phyla Amoebozoa (B); Apicomplexa (C); Kinetoplastida (D); Platyhelminthes (E); and Nematoda (F) phyla are shown. In each case, the predominant and the minor electron flow is indicated as a continuous thick arrow and a continuous thin arrow, respectively. Potential electron transfer reactions involving only redox substrates is represented by a dark (highly favoured) or light (poorly favoured) dotted arrow. From bioinformatic analysis, the presence of some components (*) is proposed. The debatable presence of a TrxR in the representatives of Kinetoplastida is indicated by a question mark (?).
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References

    1. Falkowski P.G., Godfrey L. Electrons, life, and the evolution of earth’s oxygen cycle. Philos. Trans. R. Soc. 2008;363:2705–2716. doi: 10.1098/rstb.2008.0054. - DOI - PMC - PubMed
    1. Farquhar J., Zerkle A.L., Bekker A. Geological constraints on the origin of oxygenic photosynthesis. Photosynth. Res. 2011;107:11–36. doi: 10.1007/s11120-010-9594-0. - DOI - PubMed
    1. Falkowski P.G., Isozaki Y. The Story of O2. Science. 2008;322:540–542. doi: 10.1126/science.1162641. - DOI - PubMed
    1. Schopf J.W., Oehler D.Z. How old are the eukaryotes? Science. 1976;193:47–49. doi: 10.1126/science.193.4247.47. - DOI - PubMed
    1. Thannical V.J. Oxygen in the evolution of complex life and the price we pay. Am. J. Resp. Cell Mol. Biol. 2009;40:507–510. doi: 10.1165/rcmb.2008-0360PS. - DOI - PMC - PubMed
-