Trypanothione metabolism as Drug Target for Trypanosomatids.

2020 ◽  
Vol 26 ◽  
Author(s):  
María Dolores Piñeyro ◽  
Diego G Arias ◽  
Adriana Parodi-Talice ◽  
Sergio A Guerrero ◽  
Carlos Robello
Keyword(s):  
Methionine Sulfoxide ◽  
Structural Data ◽  
Redox System ◽  
Redox Balance ◽  
Rational Drug Design ◽  
Sufficient Evidence ◽  
Mammalian Host ◽  
Neglected Diseases ◽  
High Toxicity ◽  
Methionine Sulfoxide Reductases

: Chagas Disease, African sleeping sickness, and leishmaniasis are neglected diseases caused by pathogenic trypanosomatid parasites, which have a considerable impact on morbidity and mortality in poor countries. The available drugs used as treatment have high toxicity, limited access, and can cause parasite drug resistance. Long-term treatments, added to their high toxicity, result in patients that give up therapy. Trypanosomatids presents a unique trypanothione based redox system, which is the main responsible for maintaining the redox balance. Therefore, inhibition of these essential and exclusive parasite’s metabolic pathways, absent from the mammalian host, could lead to development of more efficient and safe drugs. The system contains different redox cascades, where trypanothione and tryparedoxins, play together a central role in transferring reduced power to different enzymes, such as 2-Cys peroxiredoxins, non-selenium glutathione peroxidases, ascorbate peroxidases, glutaredoxins and methionine sulfoxide reductases, through NADPH as a source of electrons. There is sufficient evidence that this complex system is essential for parasite survival and infection. In this review, we explore what is known in terms of essentiality, kinetic and structural data, and development of inhibitors of enzymes from this trypanothione-based redox system. The recent advances and limitations in the development of lead inhibitory compounds targeting these enzymes are discussed. The combination of molecular biology, bioinformatics, genomics, and structural biology is fundamental since the knowledge of unique features of the trypanothione-dependent system will provide tools for rational drug design, in order to develop better treatments for these diseases

scholarly journals Involvement of the MetO/Msr System in Two Acer Species That Display Contrasting Characteristics during Germination

2020 ◽  
Vol 21 (23) ◽  
pp. 9197
Author(s):  
Natalia Wojciechowska ◽  
Shirin Alipour ◽  
Ewelina Stolarska ◽  
Karolina Bilska ◽  
Pascal Rey ◽  
...  
Keyword(s):  
Hydroxyl Radicals ◽  
Superoxide Anion ◽  
Redox Homeostasis ◽  
Methionine Sulfoxide ◽  
Redox System ◽  
Oxygen Species ◽  
Embryonic Axes ◽  
Methionine Sulfoxide Reductases ◽  
Germination Process ◽  
Norway Maple

The levels of methionine sulfoxide (MetO) and the abundances of methionine sulfoxide reductases (Msrs) were reported as important for the desiccation tolerance of Acer seeds. To determine whether the MetO/Msrs system is related to reactive oxygen species (ROS) and involved in the regulation of germination in orthodox and recalcitrant seeds, Norway maple and sycamore were investigated. Changes in water content, MetO content, the abundance of MsrB1 and MsrB2 in relation to ROS content and the activity of reductases depending on nicotinamide adenine dinucleotides were monitored. Acer seeds differed in germination speed—substantially higher in sycamore—hydration dynamics, levels of hydrogen peroxide, superoxide anion radicals (O2•−) and hydroxyl radicals (•OH), which exhibited peaks at different stages of germination. The MetO level dynamically changed, particularly in sycamore embryonic axes, where it was positively correlated with the levels of O2•− and the abundance of MsrB1 and negatively with the levels of •OH and the abundance of MsrB2. The MsrB2 abundance increased upon sycamore germination; in contrast, it markedly decreased in Norway maple. We propose that the ROS–MetO–Msr redox system, allowing balanced Met redox homeostasis, participates in the germination process in sycamore, which is characterized by a much higher speed compared to Norway maple.

scholarly journals Structural Insights into Interaction between Mammalian Methionine Sulfoxide Reductase B1 and Thioredoxin

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Olena Dobrovolska ◽  
Georgy Rychkov ◽  
Elena Shumilina ◽  
Kirill Nerinovski ◽  
Alexander Schmidt ◽  
...  
Keyword(s):  
Complex Formation ◽  
Methionine Sulfoxide ◽  
Redox Balance ◽  
Protein Docking ◽  
Methionine Sulfoxide Reductase ◽  
Methionine Sulfoxide Reductases ◽  
Antioxidant Defence System ◽  
Dynamics Simulations ◽  
Structural Insights ◽  
Structural Aspects

Maintenance of the cellular redox balance has vital importance for correcting organism functioning. Methionine sulfoxide reductases (Msrs) are among the key members of the cellular antioxidant defence system. To work properly, methionine sulfoxide reductases need to be reduced by their biological partner, thioredoxin (Trx). This process, according to the available kinetic data, represents the slowest step in the Msrs catalytic cycle. In the present paper, we investigated structural aspects of the intermolecular complex formation between mammalian MsrB1 and Trx. NMR spectroscopy and biocomputing were the two mostly used through the research approaches. The formation of NMR detectable MsrB1/Trx complex was monitored and studied in attempt to understand MsrB1 reduction mechanism. Using NMR data, molecular mechanics, protein docking, and molecular dynamics simulations, it was found that intermediate MsrB1/Trx complex is stabilized by interproteinβ-layer. The complex formation accompanied by distortion of disulfide bond within MsrB1 facilitates the reduction of oxidized MsrB1 as it is evidenced by the obtained data.

scholarly journals Regulation of thrombosis and vascular function by protein methionine oxidation

Blood ◽  
2015 ◽  
Vol 125 (25) ◽  
pp. 3851-3859 ◽  
Author(s):  
Sean X. Gu ◽  
Jeff W. Stevens ◽  
Steven R. Lentz
Keyword(s):  
Vascular Disease ◽  
Protein Function ◽  
Vascular Function ◽  
Vascular System ◽  
Methionine Sulfoxide ◽  
Redox Balance ◽  
Methionine Oxidation ◽  
Redox Biology ◽  
Methionine Sulfoxide Reductases ◽  
Methionine Residues

Abstract Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis.

Polyamines and Related Nitrogen Compounds in the Chemotherapy of Neglected Diseases Caused by Kinetoplastids

2018 ◽  
Vol 18 (5) ◽  
pp. 321-368 ◽  
Author(s):  
Juan A. Bisceglia ◽  
Maria C. Mollo ◽  
Nadia Gruber ◽  
Liliana R. Orelli
Keyword(s):  
Drug Targets ◽  
Redox Homeostasis ◽  
Cost Effective ◽  
Structural Features ◽  
Mammalian Host ◽  
Neglected Diseases ◽  
Nitrogen Compounds ◽  
Chemical Structures

Neglected diseases due to the parasitic protozoa Leishmania and Trypanosoma (kinetoplastids) affect millions of people worldwide, and the lack of suitable treatments has promoted an ongoing drug discovery effort to identify novel nontoxic and cost-effective chemotherapies. Polyamines are ubiquitous small organic molecules that play key roles in kinetoplastid parasites metabolism, redox homeostasis and in the normal progression of cell cycles, which differ from those found in the mammalian host. These features make polyamines attractive in terms of antiparasitic drug development. The present work provides a comprehensive insight on the use of polyamine derivatives and related nitrogen compounds in the chemotherapy of kinetoplastid diseases. The amount of literature on this subject is considerable, and a classification considering drug targets and chemical structures were made. Polyamines, aminoalcohols and basic heterocycles designed to target the relevant parasitic enzyme trypanothione reductase are discussed in the first section, followed by compounds directed to less common targets, like parasite SOD and the aminopurine P2 transporter. Finally, the third section comprises nitrogen compounds structurally derived from antimalaric agents. References on the chemical synthesis of the selected compounds are reported together with their in vivo and/or in vitro IC50 values, and structureactivity relationships within each group are analyzed. Some favourable structural features were identified from the SAR analyses comprising protonable sites, hydrophobic groups and optimum distances between them. The importance of certain pharmacophoric groups or amino acid residues in the bioactivity of polyamine derived compounds is also discussed.

scholarly journals Peptide-Bound Methionine Sulfoxide (MetO) Levels and MsrB2 Abundance Are Differentially Regulated during the Desiccation Phase in Contrasted Acer Seeds

Antioxidants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 391 ◽  
Author(s):  
Natalia Wojciechowska ◽  
Shirin Alipour ◽  
Ewelina Stolarska ◽  
Karolina Bilska ◽  
Pascal Rey ◽  
...  
Keyword(s):  
Desiccation Tolerance ◽  
Methionine Sulfoxide ◽  
Redox Status ◽  
Embryonic Axes ◽  
Seed Desiccation ◽  
Methionine Sulfoxide Reductases ◽  
Norway Maple ◽  
Orthodox Seeds ◽  
Oxidation Of Methionine ◽  
Reduced Forms

Norway maple and sycamore produce desiccation-tolerant (orthodox) and desiccation-sensitive (recalcitrant) seeds, respectively. Drying affects reduction and oxidation (redox) status in seeds. Oxidation of methionine to methionine sulfoxide (MetO) and reduction via methionine sulfoxide reductases (Msrs) have never been investigated in relation to seed desiccation tolerance. MetO levels and the abundance of Msrs were investigated in relation to levels of reactive oxygen species (ROS) such as hydrogen peroxide, superoxide anion radical and hydroxyl radical (•OH), and the levels of ascorbate and glutathione redox couples in gradually dried seeds. Peptide-bound MetO levels were positively correlated with ROS concentrations in the orthodox seeds. In particular, •OH affected MetO levels as well as the abundance of MsrB2 solely in the embryonic axes of Norway maple seeds. In this species, MsrB2 was present in oxidized and reduced forms, and the latter was favored by reduced glutathione and ascorbic acid. In contrast, sycamore seeds accumulated higher ROS levels. Additionally, MsrB2 was oxidized in sycamore throughout dehydration. In this context, the three elements •OH level, MetO content and MsrB2 abundance, linked together uniquely to Norway maple seeds, might be considered important players of the redox network associated with desiccation tolerance.

scholarly journals Overexpression of DUF538 from Wild Arachis Enhances Plant Resistance to Meloidogyne spp.

Agronomy ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 559
Author(s):  
Ana Claudia Guerra Araujo ◽  
Patricia Messenberg Guimaraes ◽  
Ana Paula Zotta Mota ◽  
Larissa Arrais Guimaraes ◽  
Bruna Medeiros Pereira ◽  
...  
Keyword(s):  
Transgenic Plants ◽  
Redox System ◽  
Redox Balance ◽  
Uncharacterized Protein ◽  
Chlorophyll Breakdown ◽  
Domain Of Unknown Function ◽  
Expression Behavior ◽  
Meloidogyne Spp ◽  
Wild Peanut ◽  
First Time

DUF538 proteins belong to a large group of uncharacterized protein families sharing the highly conserved Domain of Unknown Function (DUF). Attention has been given to DUF538 domain-containing proteins due to changes in their gene expression behavior and protein abundance during plant development and responses to stress. Putative roles attributed to DUF538 in plants under abiotic and biotic constraints include involvement in cell redox balance, chlorophyll breakdown and pectin degradation. Our previous transcriptome studies suggested that DUF538 is also involved in the resistance responses of wild Arachis species against the highly hazardous root-knot nematodes (RKNs). To clarify the role of the AsDUF538 gene from the wild peanut relative Arachis stenosperma in this interaction, we analyzed the effect of its overexpression on RKN infection in peanut and soybean hairy roots and Arabidopsis transgenic plants. AsDUF538 overexpression significantly reduced the infection in all three heterologous plant systems against their respective RKN counterparts. The distribution of AsDUF538 transcripts in RKN-infected Arachis roots and the effects of AsDUF538 overexpression on hormonal pathways and redox system in transgenic Arabidopsis were also evaluated. This is the first time that a DUF538 gene is functionally validated in transgenic plants and the earliest report on its role in plant defense against RKNs.

scholarly journals An unusual thioredoxin system in the facultative parasite Acanthamoeba castellanii

2021 ◽  
Vol 78 (7) ◽  
pp. 3673-3689
Author(s):  
David Leitsch ◽  
Alvie Loufouma Mbouaka ◽  
Martina Köhsler ◽  
Norbert Müller ◽  
Julia Walochnik
Keyword(s):  
Oxidative Stress ◽  
Stop Codon ◽  
Acanthamoeba Castellanii ◽  
Methionine Sulfoxide ◽  
Redox System ◽  
Methionine Sulfoxide Reductase ◽  
Methionine Sulfoxide Reductase A ◽  
Protein Levels ◽  
Thioredoxin System ◽  
Facultative Parasite

AbstractThe 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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