Comparative modeling of thioredoxin glutathione reductase from Schistosoma mansoni: A multifunctional target for antischistosomal therapy

Sharma, Monika; Khanna, Smriti; Bulusu, Gopalakrishnan; Mitra, Abhijit

doi:10.1016/j.jmgm.2008.10.009

Cited by 24 publications

(26 citation statements)

References 46 publications

(77 reference statements)

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“…This argument is supported by structural and modeling data study, which indicate that the putative GSSG binding pocket of TGR contains many positively charged residues and thus is more similar to GR than to TrxR suggesting that GSSG could receive electrons from the redox-active cysteine pair adjacent to FAD (Cys154/Cys159) in addition to the Cys28/Cys31 found in the Grx domain of TGR [35, 71]. Thus, it was proposed that whereas the majority of GSSG reduction occurs as the result of electrons transferred from the FAD to the neighboring Cys154/Cys159, then to the C-terminal Cys596/Sec597 of the other subunit and finally to Cys28/Cys31 in the N-terminal Grx domain of the first subunit, a small fraction of electrons might be directly transferred from the FAD site to GSSG [35, 71]. This is supported by recent analysis of a Cys28Ala/Cys31Ala mutant that retains ~4% of wild-type-TGR activity [53].…”

Section: Functions and Properties Of Tgr Enzymesmentioning

confidence: 91%

Thioredoxin glutathione reductase: Its role in redox biology and potential as a target for drugs against neglected diseases

Prast‐Nielsen

Huang

Williams

2011

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background There are two, largely autonomous antioxidant pathways in many organisms, one based on thioredoxin and one based on glutathione, with each pathway having a unique flavoprotein oxidoreductase to maintain them in a reduced state. A recently discovered protein, thioredoxin glutathione reductase (TGR) potentially connects these two pathways. In a large group of parasitic worms, responsible for hundreds of millions of infections in humans and animals, untold morbidity and significant mortality, TGR is the sole enzyme present to maintain redox balance. Scope of Review In this review, the current understanding of the biochemical properties of TGR enzymes is compared to the related enzymes thioredoxin reductase and glutathione reductase. The role of the rare amino acid selenocysteine is discussed. An overview of the potential to target TGR for drug development against a range of parasitic worms and preliminary results to identify TGR inhibitors for schistosomiasis treatment is presented. Major Conclusions TGR has properties that are both unique and common to other flavoprotein oxidoreductases. TGR plays a fundamentally different and essential role in the redox biology of parasitic flatworms. Therefore, TGR is a promising target for drug development for schistosomiasis and other trematode and cestodes infections. General Significance TGR may have differing functions in host organisms, but through analyses to understand its ability to reduce both glutathione and thioredoxin we can better understand the reaction mechanisms of an important class of enzymes. The unique properties of TGR in parasitic flatworms provide promising routes to develop new treatments for diseases.

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Section: Functions and Properties Of Tgr Enzymesmentioning

confidence: 91%

Thioredoxin glutathione reductase: Its role in redox biology and potential as a target for drugs against neglected diseases

Prast‐Nielsen

Huang

Williams

2011

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…This suggests that in TGR proteins GSSG reduction occurs at the Grx domain cysteine couple (Cys-28/Cys-31) and/or at the cysteine couple proximal to the NADPH binding site (Cys-154/Cys-159), which occurs within an amino acid sequence that is identical to that found in many authentic GR proteins [175, 181, 185]. In order to determine the site of GSSG reduction, S. mansoni TGR proteins with cysteine to alanine or cysteine to serine mutations were generated and characterized.…”

Section: The Thioredoxin Systemmentioning

confidence: 99%

“…The role of Cys-31 appears to be to facilitate the formation of the nucleophilic thiolate on Cys-28. The Cys-154/Cys-159 couple may provide the residual GR activity in the Cys28Ala variant as the electrostatic environment around this redox couple is similar to that in GR proteins and may facilitate the binding of GSSG [175, 181, 185]. In several characterized TGR proteins high concentrations of GSSG result in a transient inhibition of GSSG reduction and a delay in attaining full GR activity [178, 180, 186].…”

Section: The Thioredoxin Systemmentioning

confidence: 99%

The Redox Biology of Schistosome Parasites and Applications for Drug Development

Huang

Rigouin²,

Williams

2012

cpd

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Schistosomiasis caused by Schistosoma spp. is a serious public health concern, especially in subSaharan Africa. Praziquantel is the only drug currently administrated to treat this disease. However, praziquantel-resistant parasites have been identified in endemic areas and can be generated in the laboratory. Therefore, it is essential to find new therapeutics. Antioxidants are appealing drug targets. In order to survive in their hosts, schistosomes are challenged by reactive oxygen species from intrinsic and extrinsic sources. Schistosome antioxidant enzymes have been identified as essential proteins and novel drug targets and inhibition of the antioxidant response can lead to parasite death. Because the organization of the redox network in schistosomes is significantly different form that in humans, new drugs are being developed targeting schistosome antioxidants. In this paper the redox biology of schistosomes is discussed and their potential use as drug targets is reviewed. It is hoped that compounds targeting parasite antioxidant responses will become clinically relevant drugs in the near future. KeywordsSchistosoma; drug development; antioxidants; glutathione; thioredoxin; thioredoxin glutathione reductase Schistosomiasis (also known as bilharzia) is caused by blood-dwelling flatworms of the genus Schistosoma. Schistosomiasis is the second most important human parasitic disease after malaria, with an estimated 200 million people infected and greater than 200,000 deaths annually in tropical and subtropical areas [1][2][3]. Nearly 800 million people are at risk of infection in seventy-two counties [1]. In addition, schistosome infections lead to largely underreported chronic disabilities and morbidities, such as caloric malnutrition, growth stunting, anemia, and poor school performance, which lead to decreased quality of life and perpetuation of poverty [1][2][3]. The chronic morbidities associated with schistosomiasis can be exacerbated by co-infections with other helminths (parasitic worms, e.g., hookworms) [4] and schistosome infections can have significant impacts on the susceptibility and transmission of other infections, e.g., HIV [5,6] and malaria [7,8], and on immune responses to childhood vaccines [9]. Furthermore, S. haematobium is considered as a group 1 carcinogen leading to the development of urinary bladder cancer [10][11][12]. Intestinal schistosomiasis has been linked to hepatocellular carcinoma and colorectal cancer [13,14] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptFive species of Schistosoma parasitize humans including S. mansoni, S. japonicum, S. haematobium, S. intercalatum, and S. mekongi; the first three species have the widest geographic distribution whereas infections with the last two species only occur locally [15]. The life cycle of Schistosoma ssp. is complex [16,17] and is divided into sexual and asexual cycles. In the asexual cycle, eggs are released into water with feces or urine of infected individuals. Miracidia hatch from the eggs and th...

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“…The molecular topology file and the force-field parameters for the inhibitors were generated by the program PRO-DRG online [37]. PRODRG is an automated topology generation tool that has been widely used in the study of protein-ligand systems [29,31,38,39]. The charges of the inhibitors generated by this server have also been validated in similar compounds [29].…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Molecular dynamics simulation of the interaction between protein tyrosine phosphatase 1B and aryl diketoacid derivatives

Wang

Gao

Liu

et al. 2012

Journal of Molecular Graphics and Modelling

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Comparative modeling of thioredoxin glutathione reductase from Schistosoma mansoni: A multifunctional target for antischistosomal therapy

Cited by 24 publications

References 46 publications

Thioredoxin glutathione reductase: Its role in redox biology and potential as a target for drugs against neglected diseases

Thioredoxin glutathione reductase: Its role in redox biology and potential as a target for drugs against neglected diseases

The Redox Biology of Schistosome Parasites and Applications for Drug Development

Molecular dynamics simulation of the interaction between protein tyrosine phosphatase 1B and aryl diketoacid derivatives

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