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Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum.

Song L, Li J, Xie S, Qian C, Wang J, Zhang W, Yin X, Hua Z, Yu C - PLoS ONE (2012)

Bottom Line: These results were in good agreement with previous findings in Schistosoma mansoni and some other platyhelminths.Auranofin, a known inhibitor against TGR, caused fatal toxicity in S. japonicum adult worms in vitro and reduced worm and egg burdens in S. japonicum infected mice.This assumption is strengthened by our demonstration that the SjTGR is an essential enzyme for maintaining the thiol-disulfide redox homeostasis of S. japonicum.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory on Technology for Parasitic Disease Prevention and Control, Ministry of Health, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, People's Republic of China.

ABSTRACT

Background: Schistosomiasis remains a major public health concern affecting billions of people around the world. Currently, praziquantel is the only drug of choice for treatment of human schistosomiasis. The emergence of drug resistance to praziquantel in schistosomes makes the development of novel drugs an urgent task. Thioredoxin glutathione reductase (TGR) enzymes in Schistosoma mansoni and some other platyhelminths have been identified as alternative targets. The present study was designed to confirm the existense and the potential value of TGR as a target for development of novel antischistosomal agents in Schistosoma japonicum, a platyhelminth endemic in Asia.

Methods and findings: After cloning the S. japonicum TGR (SjTGR) gene, the recombinant SjTGR selenoprotein was purified and characterized in enzymatic assays as a multifunctional enzyme with thioredoxin reductase (TrxR), glutathione reductase (GR) and glutaredoxin (Grx) activities. Immunological and bioinformatic analyses confirmed that instead of having separate TrxR and GR proteins in mammalian, S. japonicum only encodes TGR, which performs the functions of both enzymes and plays a critical role in maintaining the redox balance in this parasite. These results were in good agreement with previous findings in Schistosoma mansoni and some other platyhelminths. Auranofin, a known inhibitor against TGR, caused fatal toxicity in S. japonicum adult worms in vitro and reduced worm and egg burdens in S. japonicum infected mice.

Conclusions: Collectively, our study confirms that a multifunctional enzyme SjTGR selenoprotein, instead of separate TrxR and GR enzymes, exists in S. japonicum. Furthermore, TGR may be a potential target for development of novel agents against schistosomes. This assumption is strengthened by our demonstration that the SjTGR is an essential enzyme for maintaining the thiol-disulfide redox homeostasis of S. japonicum.

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Related in: MedlinePlus

Protein profile of purified recombinant SjTGR.Lane 1: Purified recombinant SjTGR protein on SDS-PAGE gel stained with Commassie Blue. MW: Protein molecular weight marker.
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pone-0031456-g004: Protein profile of purified recombinant SjTGR.Lane 1: Purified recombinant SjTGR protein on SDS-PAGE gel stained with Commassie Blue. MW: Protein molecular weight marker.

Mentions: The recombinant SjTGR protein was purified with an adenosine 2′, 5′-diphosphate agarose (Sigma A3515) column, used for specific affinity purification of NADPH-binding proteins. The purity of the SjTGR protein sample was more than 95% (Fig. 4), indicating the NADPH binding capacity of the recombinant SjTGR.


Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum.

Song L, Li J, Xie S, Qian C, Wang J, Zhang W, Yin X, Hua Z, Yu C - PLoS ONE (2012)

Protein profile of purified recombinant SjTGR.Lane 1: Purified recombinant SjTGR protein on SDS-PAGE gel stained with Commassie Blue. MW: Protein molecular weight marker.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285170&req=5

pone-0031456-g004: Protein profile of purified recombinant SjTGR.Lane 1: Purified recombinant SjTGR protein on SDS-PAGE gel stained with Commassie Blue. MW: Protein molecular weight marker.
Mentions: The recombinant SjTGR protein was purified with an adenosine 2′, 5′-diphosphate agarose (Sigma A3515) column, used for specific affinity purification of NADPH-binding proteins. The purity of the SjTGR protein sample was more than 95% (Fig. 4), indicating the NADPH binding capacity of the recombinant SjTGR.

Bottom Line: These results were in good agreement with previous findings in Schistosoma mansoni and some other platyhelminths.Auranofin, a known inhibitor against TGR, caused fatal toxicity in S. japonicum adult worms in vitro and reduced worm and egg burdens in S. japonicum infected mice.This assumption is strengthened by our demonstration that the SjTGR is an essential enzyme for maintaining the thiol-disulfide redox homeostasis of S. japonicum.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory on Technology for Parasitic Disease Prevention and Control, Ministry of Health, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, People's Republic of China.

ABSTRACT

Background: Schistosomiasis remains a major public health concern affecting billions of people around the world. Currently, praziquantel is the only drug of choice for treatment of human schistosomiasis. The emergence of drug resistance to praziquantel in schistosomes makes the development of novel drugs an urgent task. Thioredoxin glutathione reductase (TGR) enzymes in Schistosoma mansoni and some other platyhelminths have been identified as alternative targets. The present study was designed to confirm the existense and the potential value of TGR as a target for development of novel antischistosomal agents in Schistosoma japonicum, a platyhelminth endemic in Asia.

Methods and findings: After cloning the S. japonicum TGR (SjTGR) gene, the recombinant SjTGR selenoprotein was purified and characterized in enzymatic assays as a multifunctional enzyme with thioredoxin reductase (TrxR), glutathione reductase (GR) and glutaredoxin (Grx) activities. Immunological and bioinformatic analyses confirmed that instead of having separate TrxR and GR proteins in mammalian, S. japonicum only encodes TGR, which performs the functions of both enzymes and plays a critical role in maintaining the redox balance in this parasite. These results were in good agreement with previous findings in Schistosoma mansoni and some other platyhelminths. Auranofin, a known inhibitor against TGR, caused fatal toxicity in S. japonicum adult worms in vitro and reduced worm and egg burdens in S. japonicum infected mice.

Conclusions: Collectively, our study confirms that a multifunctional enzyme SjTGR selenoprotein, instead of separate TrxR and GR enzymes, exists in S. japonicum. Furthermore, TGR may be a potential target for development of novel agents against schistosomes. This assumption is strengthened by our demonstration that the SjTGR is an essential enzyme for maintaining the thiol-disulfide redox homeostasis of S. japonicum.

Show MeSH
Related in: MedlinePlus