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Article: A small molecule inhibitor of Endoplasmic Reticulum Oxidation 1 (ERO1) with selectively reversible thiol reactivity

TitleA small molecule inhibitor of Endoplasmic Reticulum Oxidation 1 (ERO1) with selectively reversible thiol reactivity
Authors
Issue Date2010
Citation
Journal of Biological Chemistry, 2010, v. 285, n. 27, p. 20993-21003 How to Cite?
AbstractEndoplasmic reticulum oxidation 1 (ERO1) is a conserved eukaryotic flavin adenine nucleotide-containing enzyme that promotes disulfide bond formation by accepting electrons from reduced protein disulfide isomerase (PDI) and passing them on to molecular oxygen. Although disulfide bond formation is an essential process, recent experiments suggest a surprisingly broad tolerance to genetic manipulations that attenuate the rate of disulfide bond formation and that a hyperoxidizing ER may place stressed cells at a disadvantage. In this study, we report on the development of a high throughput in vitro assay for mammalian ERO1α activity and its application to identify small molecule inhibitors. The inhibitor EN460 (IC50, 1.9 μM) interacts selectively with the reduced, active form of ERO1α and prevents its reoxidation. Despite rapid and promiscuous reactivity with thiolates, EN460 exhibits selectivity for ERO1. This selectivity is explained by the rapid reversibility of the reaction of EN460 with unstructured thiols, in contrast to the formation of a stable bond with ERO1α followed by displacement of bound flavin adenine dinucleotide from the active site of the enzyme. Modest concentrations of EN460 and a functionally related inhibitor, QM295, promote signaling in the unfolded protein response and precondition cells against severe ER stress. Together, these observations point to the feasibility of targeting the enzymatic activity of ERO1α with small molecule inhibitors. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/205776
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorBlais, Jaime D.-
dc.contributor.authorChin, Kingtung-
dc.contributor.authorZito, Ester-
dc.contributor.authorZhang, Yuhong-
dc.contributor.authorHeldman, Nimrod-
dc.contributor.authorHarding, Heather P.-
dc.contributor.authorFass, Deborah-
dc.contributor.authorThorpe, Colin-
dc.contributor.authorRon, David-
dc.date.accessioned2014-10-06T08:02:20Z-
dc.date.available2014-10-06T08:02:20Z-
dc.date.issued2010-
dc.identifier.citationJournal of Biological Chemistry, 2010, v. 285, n. 27, p. 20993-21003-
dc.identifier.issn0021-9258-
dc.identifier.urihttp://hdl.handle.net/10722/205776-
dc.description.abstractEndoplasmic reticulum oxidation 1 (ERO1) is a conserved eukaryotic flavin adenine nucleotide-containing enzyme that promotes disulfide bond formation by accepting electrons from reduced protein disulfide isomerase (PDI) and passing them on to molecular oxygen. Although disulfide bond formation is an essential process, recent experiments suggest a surprisingly broad tolerance to genetic manipulations that attenuate the rate of disulfide bond formation and that a hyperoxidizing ER may place stressed cells at a disadvantage. In this study, we report on the development of a high throughput in vitro assay for mammalian ERO1α activity and its application to identify small molecule inhibitors. The inhibitor EN460 (IC50, 1.9 μM) interacts selectively with the reduced, active form of ERO1α and prevents its reoxidation. Despite rapid and promiscuous reactivity with thiolates, EN460 exhibits selectivity for ERO1. This selectivity is explained by the rapid reversibility of the reaction of EN460 with unstructured thiols, in contrast to the formation of a stable bond with ERO1α followed by displacement of bound flavin adenine dinucleotide from the active site of the enzyme. Modest concentrations of EN460 and a functionally related inhibitor, QM295, promote signaling in the unfolded protein response and precondition cells against severe ER stress. Together, these observations point to the feasibility of targeting the enzymatic activity of ERO1α with small molecule inhibitors. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.-
dc.languageeng-
dc.relation.ispartofJournal of Biological Chemistry-
dc.titleA small molecule inhibitor of Endoplasmic Reticulum Oxidation 1 (ERO1) with selectively reversible thiol reactivity-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1074/jbc.M110.126599-
dc.identifier.pmid20442408-
dc.identifier.scopuseid_2-s2.0-77954225337-
dc.identifier.volume285-
dc.identifier.issue27-
dc.identifier.spage20993-
dc.identifier.epage21003-
dc.identifier.eissn1083-351X-
dc.identifier.isiWOS:000279228600063-

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