title: Is the Peroxiredoxin 2/Thioredoxin/Thioredoxin Reductase system in human erythrocytes designed for redox signaling?
abstract: In human erythrocytes H2O2 is mainly consumed by glutathione peroxidase, catalase and peroxiredoxin 2 (Prx2). Our previous analyses indicate that Prx2's peroxidase activity is subjected to a strong but quickly reversible inhibition (see companion abstract). If this activity is inhibited then the main role of Prx2 cannot be to eliminate H2O2. What functional advantages could then such an inhibition confer?We set up and validated a kinetic model of H2O2 metabolism human erythrocytes that shows quantitative agreement with extensive experimental observations. We then applied it to analyze the behavior of Prx2 and Trx under the H2O2 exposure dynamics that erythrocytes face in circulation. The significance of Prx2 inhibition was assessed by comparing the behavior of this model with that of an otherwise identical model lacking inhibition.Our analysis shows that Prx2 inhibition leads to 25-40% lower NADPH consumption under low to moderately high H2O2 supply (<0.8µM H2O2/s). Further, the inhibition extends the range where the concentrations of potential redox signaling readouts - H2O2, Prx2 sulfenic acid, Prx2 disulfide and Trx disulfide- show a proportional response to changes in H2O2 supply, covering practically the whole physiological range of the latter. This is desirable for analogic signal transduction and allows the Prx2/Trx/TrxR system to reliably transduce changes in H2O2 supply as changes in thiol oxidation. Finally, the inhibition allows other less abundant peroxiredoxins in the erythrocyte to be oxidized by H2O2 at physiological H2O2 supplies.Altogether, these results suggest that the postulated reversible inhibition of Prx2's peroxidase facilitates signal transduction by the peroxiredoxins and spares NADPH.We acknowledge: fellowship SFRH/BD/51199/2010, grants PEst-C/SAU/LA0001/2013-2014, PEst-OE/QUI/UI0612/2013, PEst-OE/QUI/UI0313/2014, and FCOMP-01-0124-FEDER-020978 co-financed by FEDER through the COMPETE program and by FCT (project PTDC/QUI-BIQ/119657/2010).
authors.affiliation: CNC (Center for Neuroscience and Cell Biology), University of Coimbra, Portugal. Electronic address: rui.benfeitas@gmail.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Benfeitas
authors.affiliation: CNC (Center for Neuroscience and Cell Biology), University of Coimbra, Portugal.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Selvaggio
authors.affiliation: DQB (Centro de Química e Bioquímica), Departamento de Química e Bioquímica, Universidade de Lisboa, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Antunes
authors.affiliation: CNC (Center for Neuroscience and Cell Biology), University of Coimbra, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Coelho
authors.affiliation: CNC (Center for Neuroscience and Cell Biology), University of Coimbra, Portugal.
authors.forename: Armindo
authors.initials: A
authors.lastname: Salvador