Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum.
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3285170?pdf=render |
| _version_ | 1818031136192856064 |
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| author | LiJun Song JiaHuang Li ShuYing Xie ChunYan Qian Jie Wang Wei Zhang Xuren Yin ZiChun Hua ChuanXin Yu |
| author_facet | LiJun Song JiaHuang Li ShuYing Xie ChunYan Qian Jie Wang Wei Zhang Xuren Yin ZiChun Hua ChuanXin Yu |
| author_sort | LiJun Song |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T05:46:40Z |
| format | Article |
| id | doaj.art-8f8aba2a0b614efbbecbc04202ee8986 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T05:46:40Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-8f8aba2a0b614efbbecbc04202ee89862022-12-22T02:00:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0172e3145610.1371/journal.pone.0031456Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum.LiJun SongJiaHuang LiShuYing XieChunYan QianJie WangWei ZhangXuren YinZiChun HuaChuanXin YuBACKGROUND: 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.http://europepmc.org/articles/PMC3285170?pdf=render |
| spellingShingle | LiJun Song JiaHuang Li ShuYing Xie ChunYan Qian Jie Wang Wei Zhang Xuren Yin ZiChun Hua ChuanXin Yu Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum. PLoS ONE |
| title | Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum. |
| title_full | Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum. |
| title_fullStr | Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum. |
| title_full_unstemmed | Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum. |
| title_short | Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum. |
| title_sort | thioredoxin glutathione reductase as a novel drug target evidence from schistosoma japonicum |
| url | http://europepmc.org/articles/PMC3285170?pdf=render |
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