title: Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum.
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.
  
  
  RESULTS
  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.
authors.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.
authors.forename: LiJun
authors.initials: L
authors.lastname: Song
authors.forename: JiaHuang
authors.initials: J
authors.lastname: Li
authors.forename: ShuYing
authors.initials: S
authors.lastname: Xie
authors.forename: ChunYan
authors.initials: C
authors.lastname: Qian
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xuren
authors.initials: X
authors.lastname: Yin
authors.forename: ZiChun
authors.initials: Z
authors.lastname: Hua
authors.forename: ChuanXin
authors.initials: C
authors.lastname: Yu
mesh_terms: D000818:Animals; D001310:Auranofin / Q000737:chemistry; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020224:Expressed Sequence Tags; D006376:Helminths; D006706:Homeostasis; D007700:Kinetics; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012549:Schistosoma japonicum / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000378:metabolism*; D012552:Schistosomiasis / Q000628:therapy*; D012643:Selenium / Q000737:chemistry
chemical_list: D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D011994:Recombinant Proteins; D001310:Auranofin; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase; D012643:Selenium