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dc.contributor.authorRackham, Oliveren_US
dc.contributor.authorJ. Shearwood, Anne-Marieen_US
dc.contributor.authorThyer, Rossen_US
dc.contributor.authorMcNamara, Elyshiaen_US
dc.contributor.authorM.K. Davies, Stefanen_US
dc.contributor.authorA. Callus, Bernarden_US
dc.contributor.authorMiranda-Vizuete, Antonioen_US
dc.contributor.authorBerners-Price, Sueen_US
dc.contributor.authorCheng, Qingen_US
dc.contributor.authorS.J. Arner, Eliasen_US
dc.contributor.authorFilipovska, Aleksandraen_US
dc.date.accessioned2017-04-24T08:48:31Z
dc.date.available2017-04-24T08:48:31Z
dc.date.issued2011en_US
dc.date.modified2011-08-11T06:03:16Z
dc.identifier.issn0891-5849en_US
dc.identifier.doi10.1016/j.freeradbiomed.2010.12.015en_AU
dc.identifier.urihttp://hdl.handle.net/10072/39826
dc.description.abstractThe cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) and thioredoxins (Trx1 and Trx2) are key components of the mammalian thioredoxin system that is important for antioxidant defense and redox regulation of cell function. TrxR1 and TrxR2 are selenoproteins generally considered have comparable properties, but functionally separated through their different compartments. To compare their properties we expressed recombinant human TrxR1 and TrxR2 and determined their substrate specificities and inhibition by metal compounds. TrxR2 preferred its endogenous substrate Trx2 over Trx1, while TrxR1 efficiently reduced both Trx1 and Trx2. TrxR2 displayed strikingly lower activity with DTNB, lipoamide and the quinone substrate juglone compared to TrxR1, and TrxR2 could not reduce lipoic acid. However, Sec-deficient two-amino acid truncated TrxR2 was almost as efficient as full-length TrxR2 in reduction of DTNB. We found that the gold(I) compound auranofin efficiently inhibited both full-length TrxR1 and TrxR2 and truncated TrxR2. In contrast, some newly synthesized gold(I) compounds and cisplatin inhibited only full-length TrxR1 or TrxR2, but not truncated TrxR2. Surprisingly, one gold(I) compound, [Au(d2pype)(2)]Cl, was a better inhibitor for TrxR1 while another, [(iPr(2)Im)(2)Au]Cl, mainly inhibited TrxR2. These compounds also inhibited TrxR activity in the cytoplasm and mitochondria of cells, but their cytotoxicity was not always dependent on the proapoptotic proteins Bax and Bak. In conclusion, this study reveals significant differences between human TrxR1 and TrxR2 in substrate specificities and metal compound inhibition in vitro and in cells, which may be exploited for development of specific TrxR1- or TrxR2-targeting drugs.en_US
dc.description.peerreviewedYesen_US
dc.description.publicationstatusYesen_AU
dc.languageEnglishen_US
dc.language.isoen_AU
dc.publisherElsevieren_US
dc.publisher.placeUnited Statesen_US
dc.relation.ispartofstudentpublicationNen_AU
dc.relation.ispartofpagefrom689en_US
dc.relation.ispartofpageto699en_US
dc.relation.ispartofissue6en_US
dc.relation.ispartofjournalFree Radical Biology and Medicineen_US
dc.relation.ispartofvolume50en_US
dc.rights.retentionYen_AU
dc.subject.fieldofresearchBiochemistry and Cell Biology not elsewhere classifieden_US
dc.subject.fieldofresearchcode060199en_US
dc.titleSubstrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: Implications for development of specific inhibitorsen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.date.issued2011
gro.hasfulltextNo Full Text


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