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dc.contributor.authorRackham, Oliver
dc.contributor.authorShearwood, Anne-Marie J
dc.contributor.authorThyer, Ross
dc.contributor.authorMcNamara, Elyshia
dc.contributor.authorDavies, Stefan MK
dc.contributor.authorCallus, Bernard A
dc.contributor.authorMiranda-Vizuete, Antonio
dc.contributor.authorBerners-Price, Susan J
dc.contributor.authorCheng, Qing
dc.contributor.authorArner, Elias SJ
dc.contributor.authorFilipovska, Aleksandra
dc.date.accessioned2018-02-13T03:13:47Z
dc.date.available2018-02-13T03:13:47Z
dc.date.issued2011
dc.date.modified2011-08-11T06:03:16Z
dc.identifier.issn0891-5849
dc.identifier.doi10.1016/j.freeradbiomed.2010.12.015
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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.publisher.placeUnited States
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom689
dc.relation.ispartofpageto699
dc.relation.ispartofissue6
dc.relation.ispartofjournalFree Radical Biology and Medicine
dc.relation.ispartofvolume50
dc.relation.urihttp://purl.org/au-research/grants/ARC/DP0986318
dc.relation.grantIDDP0986318
dc.relation.fundersARC
dc.rights.retentionY
dc.subject.fieldofresearchBiochemistry and Cell Biology not elsewhere classified
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchBiochemistry and Cell Biology
dc.subject.fieldofresearchMedical Biochemistry and Metabolomics
dc.subject.fieldofresearchcode060199
dc.subject.fieldofresearchcode0304
dc.subject.fieldofresearchcode0601
dc.subject.fieldofresearchcode1101
dc.titleSubstrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: Implications for development of specific inhibitors
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.date.issued2011
gro.hasfulltextNo Full Text
gro.griffith.authorBerners-Price, Sue J.


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