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Les Méthionine Sulfoxyde Réductases de classe A : catalyse, spécificité structurale et relations structure-fonction

Abstract : Methionine Sulfoxide Reductases (Msr) play an essential role in cell defences against oxidative stress and in virulence of pathogenic bacteria of Neisseria genius. There structurally-unrelated classes of Msrs, called MsrA and MsrB, specifie for the S and the R epimer of the sulfox ide function, respectively. Both Msrs present a similar catalytic mechanism, which implies the successive formation of a sulfenic acid intermediate and of an intra disulfide bond, finally reduced by thioredoxin (Trx). The studies of the MsrA domain from Neisseria meningitidis PilB protein demonstrated that: 1) the reductase step is fast and rate-determining in the process leading to the formation of the intramolecular disulfide bond, the overall rate-limiting step being associated with the reduction of MsrA by Trx, 2) the substrate binds to the active site with its sulfoxide function largely polarized, via stabilizing interactions with invariant residues E94, Y82 and Y134, and participates via the -partial-lpositive charge borne by the sulfur of the sulfoxide to the activation of the catalytic Cys and : 3) C198 is the MsrA Cys engaged in the transient intermolecular disulfide bond formed with Trx during MsrA recycling. The analysis of the enzymatic results coupled with the results of theoretical chemistry and the three-dimensional structures of reduced, complexed with substrate, sulfenic acid intermediate and disulfide bond oxidized forms of MsrA obtained by X-ray crystallography and NMR led us to propose an original scenario of the MsrA catalytic mechanism.
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Mathias Antoine. Les Méthionine Sulfoxyde Réductases de classe A : catalyse, spécificité structurale et relations structure-fonction. Biologie moléculaire. Université Henri Poincaré - Nancy 1, 2006. Français. ⟨NNT : 2006NAN10169⟩. ⟨tel-01746971⟩

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