Discovery of a new non-substrate inhibitor of the 26.5 kDa glutathione transferase from Taenia solium by virtual screening

2020 ◽  
Vol 100 ◽  
pp. 107707
Author(s):  
Ponciano García-Gutiérrez ◽  
Rafael A. Zubillaga ◽  
Alexandro Téllez-Plancarte ◽  
Roberto Flores-López ◽  
Menandro Camarillo-Cadena ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Glutathione Transferase ◽  
Taenia Solium ◽  
Substrate Inhibitor

scholarly journals Development of New Drugs to Treat Taenia solium Cysticercosis: Targeting 26 kDa Glutathione Transferase

2021 ◽  
Author(s):  
Rafael A. Zubillaga ◽  
Lucía Jiménez ◽  
Ponciano García-Gutiérrez ◽  
Abraham Landa
Keyword(s):  
Glutathione Transferase ◽  
Competitive Inhibition ◽  
Taenia Solium ◽  
Parasitic Infection ◽  
Docking Simulation ◽  
New Drugs ◽  
Inhibition Mechanism ◽  
Cytosolic Glutathione ◽  
The Central Nervous System ◽  
A Site

Taenia solium causes neurocysticercosis, a parasitic infection of the central nervous system in humans. The costs of management, treatment, and diagnosis of patients with neurocysticercosis are high, and some patients do not respond to the currently available treatments. Helminth cytosolic glutathione transferases (GSTs) are essential enzymes involved in the regulation of immune responses, transport, and detoxification. In T. solium, three cytosolic GSTs with molecular masses of 26.5 (Ts26GST), 25.5 (Ts25GST), and 24.3 kDa (TsMσGST), classified as mu-alpha, mu and sigma GST-classes, respectively, constitute the main detoxification system, and they may be immune targets for the development of vaccines and new anthelmintics. We performed a successful virtual screen, and identified I7, a novel selective inhibitor of Ts26GST that showed a non-competitive inhibition mechanism towards substrate glutathione with a Ki of 55.7 mM and mixed inhibition towards the electrophilic substrate 1-chloro-2,4-dinitrobenzene with a Ki of 8.64 mM. Docking simulation studies showed that I7 can bind to a site that is adjacent to the electrophilic site and the furthest from the glutathione site. This new inhibitor of Ts26GST will be used as a lead molecule to develop new effective and safe drugs against diseases caused by T. solium.

scholarly journals Taenia solium glutathione transferase fraction activates macrophages and favors the development of Th1-type response

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Vera Teresa Vega-Angeles ◽  
Luis I. Terrazas ◽  
Yadira Ledesma-Soto ◽  
Lucía Jiménez ◽  
Abraham Landa
Keyword(s):  
Cell Proliferation ◽  
Plasma Membranes ◽  
Cell Activation ◽  
Glutathione Transferase ◽  
Taenia Solium ◽  
Peritoneal Macrophages ◽  
Cd4 Cells ◽  
Ifn Γ ◽  
Type Response

AbstractGlutathione (GSH) transferase (GST) is an essential enzyme in cestodes for the detoxification of xenobiotics. In Taenia solium, two GSTs (Ts25GST and Ts26GST kDa) were isolated as a fraction (SGSTF) by GSH-Sepharose-4B. Both are located on the tegument. Immunization assays with SGSTF reduced up to 90% of the parasitic load in a murine model of cysticercosis. It prompted us to investigate how SGSTF induces this protective immune response. To test it, we exposed peritoneal macrophages to SGSTF for 24 h; such exposure favored the production of IL-12, TNF, and IL-10 as well as the expression of nitric oxide synthase 2 inducible (Nos2) and CD86, but did not induce the expression of chitinase-like 3 (Chil3). Confocal microscopy showed that the macrophages internalize the SGSTF which co-localized after 1 h with MHC-II in their plasma membranes. Macrophages exposed to SGSTF and co-cultured with anti-CD3 pre-activated T CD4+ cells, enhanced the proliferation of CD4+ cells, induced high interferon-γ (IFN-γ) secretion, and elevated the expression of CD25 and CD69, molecules associated with cell activation. Similar assay using T CD4+ cells from DO11.10 mice and ovalbumin (OVA) peptide+SGSTF as stimuli, showed enhanced cell proliferation and OVA-specific IFN-γ secretion. These data are in-line with those indicating that the P1, P5, and P6 peptides of Schistosoma japonicum 28GST highly promote T-cell proliferation and Th1 response in vitro. We found that such peptides are also present on Ts25GST and Ts26GST. It suggests that SGSTF activates peritoneal macrophages to a classically activated-like phenotype, and that these macrophages induce the differentiation of T CD4+ cells toward a Th1-type response.

scholarly journals Paradoxical inhibition of rat glutathione transferase 4-4 by indomethacin explained by substrate-inhibitor-enzyme complexes in a random-order sequential mechanism

1988 ◽  
Vol 250 (3) ◽  
pp. 705-711 ◽  
Author(s):  
U H Danielson ◽  
B Mannervik
Keyword(s):  
Glutathione Transferase ◽  
Random Order ◽  
Competitive Inhibitor ◽  
Glutathione Transferases ◽  
Low Concentrations ◽  
Standard Assay ◽  
Sequential Mechanism ◽  
Substrate Inhibitor ◽  
Enzyme Complexes ◽  
Assay Conditions

Under standard assay conditions, with 1-chloro-2,4-dinitrobenzene (CDNB) as electrophilic substrate, rat glutathione transferase 4-4 is strongly inhibited (I50 = 1 microM) by indomethacin. No other glutathione transferase investigated is significantly inhibited by micromolar concentrations of indomethacin. Paradoxically, the strong inhibition of glutathione transferase 4-4 was dependent on high (millimolar) concentrations of CDNB; at low concentrations of this substrate or with other substrates the effect of indomethacin on the enzyme was similar to the moderate inhibition noted for other glutathione transferases. In general, the inhibition of glutathione transferases can be explained by a random-order sequential mechanism, in which indomethacin acts as a competitive inhibitor with respect to the electrophilic substrate. In the specific case of glutathione transferase 4-4 with CDNB as substrate, indomethacin binds to enzyme-CDNB and enzyme-CDNB-GSH complexes with an even greater affinity than to the corresponding complexes lacking CDNB. Under presumed physiological conditions with low concentrations of electrophilic substrates, indomethacin is not specific for glutathione transferase 4-4 and may inhibit all forms of glutathione transferase.

Novel inhibitors to Taenia solium Cu/Zn superoxide dismutase identified by virtual screening

2011 ◽  
Vol 25 (12) ◽  
pp. 1135-1145 ◽  
Author(s):  
P. García-Gutiérrez ◽  
A. Landa-Piedra ◽  
A. Rodríguez-Romero ◽  
R. Parra-Unda ◽  
A. Rojo-Domínguez
Keyword(s):  
Superoxide Dismutase ◽  
Virtual Screening ◽  
Taenia Solium

scholarly journals Evaluation of recombinant glutathione transferase 26 kDa, thioredoxin-1, and endophilin B1 of Taenia solium in the diagnosis of human neurocysticercosis

Acta Tropica ◽  
2021 ◽  
pp. 106294
Author(s):  
Lucía Jiménez ◽  
Narda Karina Castro-Nolasco ◽  
Agnès Fleury ◽  
Sylvia Páz Díaz-Camacho ◽  
Alicia Ochoa-Sánchez ◽  
...  
Keyword(s):  
Glutathione Transferase ◽  
Taenia Solium ◽  
Thioredoxin 1

Evaluation of the non-catalytic binding function of Ts26GST a glutathione transferase isoform of Taenia solium

2014 ◽  
Vol 138 ◽  
pp. 63-70 ◽  
Author(s):  
A. Plancarte ◽  
J.R. Romero ◽  
G. Nava ◽  
H. Reyes ◽  
M. Hernández
Keyword(s):  
Glutathione Transferase ◽  
Taenia Solium ◽  
Binding Function

Two glutathione transferase isoforms isolated from juvenile cysts ofTaenia crassiceps: identification, purification and characterization

2017 ◽  
Vol 92 (6) ◽  
pp. 687-695 ◽  
Author(s):  
G. Maldonado ◽  
G. Nava ◽  
A. Plancarte
Keyword(s):  
Glutathione Transferase ◽  
Taenia Solium ◽  
Single Step ◽  
Glutathione Transferases ◽  
Mass Spectrometry Analysis ◽  
Purification And Characterization ◽  
Spectrometry Analysis ◽  
Enzyme Subunits ◽  
Molecular Masses ◽  
Potential Use

AbstractWe identified and characterized the first two glutathione transferases (GSTs) isolated from juvenile cysts ofTaenia crassiceps(EC 2.5.1.18). The two glutathione transferases (TcGST1 and TcGST2) were purified in a single-step protocol using glutathione (GSH)-sepharose chromatography in combination with a GSH gradient. The specific activities of TcGST1 and TcGST2 were 26 U mg−1and 19 U mg−1, respectively, both at 25°C and pH 6.5 with 1-chloro-2,4-dinitrobenzene (CDNB) and GSH as substrates. TheKm(CDNB)andKcat(CDNB)values for TcGST1 and TcGST2 (0.86 μmand 62 s−1; 1.03 μmand 1.97 s−1, respectively) andKm(GSH)andKcat(GSH)values for TcGST1 and TcGST2 (0.55 μmand 11.61 s−1; 0.3 μmand 32.3 s−1, respectively) were similar to those reported for mammalian and helminth GSTs. Mass spectrometry analysis showed that eight peptides from each of the two parasite transferases were a match for gi|29825896 glutathione transferase (Taenia solium), confirming that both enzymes are GSTs. The relative molecular masses were 54,000 ± 0.9 for the native enzymes and 27,500 ± 0.5 for the enzyme subunits. Thus, TcGST1 and TcGST2 are dimeric proteins. Optimal TcGST1 and TcGST2 activities were observed at pH 8.5 in the range of 20–55°C and pH 7.5 at 35–40°C, respectively. TcGST1 and TcGST2 were inhibited by cibacron blue (CB), bromosulphophthalein (BST), rose bengal (RB), indomethacin and haematin (Hm) with 50% inhibitory concentrations (IC50) in the μmrange. TcGST1 was inhibited in a non-competitive manner by all tested inhibitors with the exception of indomethacin, which was uncompetitive. The discovery of these new GSTs facilitates the potential use ofT. crassicepsas a model to investigate multifunctional GSTs.

A novel sigma-like glutathione transferase of Taenia solium metacestode☆

2010 ◽  
Vol 40 (9) ◽  
pp. 1097-1106 ◽  
Author(s):  
Hung Anh Nguyen ◽  
Young-An Bae ◽  
Eung-Goo Lee ◽  
Seon-Hee Kim ◽  
Sylvia Paz Diaz-Camacho ◽  
...  
Keyword(s):  
Glutathione Transferase ◽  
Taenia Solium
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