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Enzymologie du mécanisme de régulation des Peroxyrédoxines par suroxydation au cours de la signalisation cellulaire redox

Abstract : Peroxiredoxins from the Prx1 subfamily (Prx) are moonlighting peroxidases that operate in peroxide signaling and are regulated by sulfinylation. Prxs offer a major model of protein−thiol oxidative modification. They react with H2O2 to form a sulfenic acid intermediate that either engages into a disulfide bond, committing the enzyme into its peroxidase cycle, or again reacts with peroxide to produce a sulfinic acid that inactivates the enzyme. Sensitivity to sulfinylation depends on the kinetics of these two competing reactions and is critically influenced by a structural transition from a fully folded (FF) to locally unfolded (LU) conformation. Analysis of the reaction of the Tsa1 Saccharomyces cerevisiae Prx with H2O2 by Trp fluorescence-based rapid kinetics revealed a process linked to the FF/LU transition that is kinetically distinct from disulfide formation and suggested that sulfenate formation facilitates local unfolding. Use of mutants of distinctive sensitivities and of different peroxide substrates showed that sulfinylation sensitivity is not coupled to the resolving step kinetics but depends only on the sulfenic acid oxidation and FF-to-LU transition rate constants. From these two parameters, the relative sensitivities of Prxs toward hyperoxidation with different substrates can be predicted, as confirmed by in vitro and in vivo patterns.
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Submitted on : Friday, October 9, 2020 - 3:55:28 PM
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Alexandre Kriznik. Enzymologie du mécanisme de régulation des Peroxyrédoxines par suroxydation au cours de la signalisation cellulaire redox. Biochimie, Biologie Moléculaire. Université de Lorraine, 2020. Français. ⟨NNT : 2020LORR0083⟩. ⟨tel-02962966⟩

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