Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/46631
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dc.contributor.authorSelvaggio, Gianluca-
dc.contributor.authorCoelho, Pedro M. B. M.-
dc.contributor.authorSalvador, Armindo-
dc.date.accessioned2018-01-22T10:10:09Z-
dc.date.available2018-01-22T10:10:09Z-
dc.date.issued2017-12-21-
dc.identifier.urihttps://hdl.handle.net/10316/46631-
dc.description.abstractThe system (PTTRS) formed by typical 2-Cys peroxiredoxins (Prx), thioredoxin (Trx), Trx reductase (TrxR), and sulfiredoxin (Srx) is central in antioxidant protection and redox signaling in the cytoplasm of eukaryotic cells. Understanding how the PTTRS integrates these functions requires tracing phenotypes to molecular properties, which is non-trivial. Here we analyze this problem based on a model that captures the PTTRS' conserved features. We have mapped the conditions that generate each distinct response to H2O2 supply rates (vsup), and estimated the parameters for thirteen human cell types and for Saccharomyces cerevisiae. The resulting composition-to-phenotype map yielded the following experimentally testable predictions. The PTTRS permits many distinct responses including ultra-sensitivity and hysteresis. However, nearly all tumor cell lines showed a similar response characterized by limited Trx-S- depletion and a substantial but self-limited gradual accumulation of hyperoxidized Prx at high vsup. This similarity ensues from strong correlations between the TrxR, Srx and Prx activities over cell lines, which contribute to maintain the Prx-SS reduction capacity in slight excess over the maximal steady state Prx-SS production. In turn, in erythrocytes, hepatocytes and HepG2 cells high vsup depletes Trx-S- and oxidizes Prx mainly to Prx-SS. In all nucleated human cells the Prx-SS reduction capacity defined a threshold separating two different regimes. At sub-threshold vsup the cytoplasmic H2O2 concentration is determined by Prx, nM-range and spatially localized, whereas at supra-threshold vsup it is determined by much less active alternative sinks and μM-range throughout the cytoplasm. The yeast shows a distinct response where the Prx Tsa1 accumulates in sulfenate form at high vsup. This is mainly due to an exceptional stability of Tsa1's sulfenate. The implications of these findings for thiol redox regulation and cell physiology are discussed. All estimates were thoroughly documented and provided, together with analytical approximations for system properties, as a resource for quantitative redox biology.por
dc.description.sponsorshipThis work was funded by fellowship SFRH/BD/51576/2011 and grants UID/NEU/04539 COMPETE (POCI-01-0145-FEDER-007440), PEst-OE/QUI/UI0612/2013, and FCOMP-01-0124- FEDER-020978 financed by FEDER through the “Programa Operacional Factores de Competitividade, COMPETE” and by national funds through “FCT, Fundação para a Ciência e a Tecnologia” (project PTDC/QUI-BIQ/119657/2010).-
dc.language.isoporpor
dc.publisherElsevierpor
dc.rightsopenAccesspor
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/por
dc.subjectRedox relayspor
dc.subjectRedox signalingpor
dc.subjectThiol redox regulationpor
dc.subjectQuantitative redox biologypor
dc.subjectSystems design space methodologypor
dc.titleMapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin – Thioredoxin system. 1. Understanding commonalities and differences among cell typespor
dc.typearticle-
degois.publication.firstPage297por
degois.publication.lastPage315por
degois.publication.titleRedox Biologypor
dc.relation.publisherversionhttp://www.sciencedirect.com/science/article/pii/S2213231717308819?via%3Dihubpor
dc.peerreviewedyespor
dc.identifier.doi10.1016/j.redox.2017.12.008por
degois.publication.volume15por
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.grantfulltextopen-
item.openairetypearticle-
item.languageiso639-1pt-
item.fulltextCom Texto completo-
item.cerifentitytypePublications-
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
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