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Characterization of the Amino Acids Involved in Substrate Specificity of Methionine Sulfoxide Reductase A

Abstract : Methionine sulfoxide reductases (Msrs) are ubiquitous enzymes that catalyze the thioredoxin-dependent reduction of methionine sulfoxide (MetSO) back to methionine. In vivo, Msrs are essential in protecting cells against oxidative damages on proteins and in the virulence of some bacteria. There exists two structurally unrelated classes of Msrs. MsrAs are stereo-specific toward the S epimer on the sulfur of the sulfoxide, whereas MsrBs are specific toward the R isomer. Both classes of Msrs display a similar catalytic mechanism of sulfoxide reduction by thiols via the sulfenic acid chemistry and a better affinity for protein-bound MetSO than for free MetSO. Recently, the role of the amino acids implicated in the catalysis of the reductase step of Neisseria meningitidis MsrA was determined. In the present study, the invariant amino acids potentially involved in substrate binding, i.e. Phe-52, Trp-53, Asp-129, His-186, Tyr-189, and Tyr-197, were substituted. The catalytic parameters under steady-state conditions and of the reductase step of the mutated MsrAs were determined and compared with those of the wild type. Altogether, the results support the presence of at least two binding subsites. The first one, whose contribution is major in the efficiency of the reductase step and in which the ϵ-methyl group of MetSO binds, is the hydrophobic pocket formed by Phe-52 and Trp-53, the position of the indole ring being stabilized by interactions with His-186 and Tyr-189. The second subsite composed of Asp-129 and Tyr-197 contributes to the binding of the main chain of the substrate but to a lesser extent.
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Contributor : Sandrine BOSCHI-MULLER Connect in order to contact the contributor
Submitted on : Tuesday, January 23, 2018 - 11:51:39 AM
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J. Biol. Chem.-2007-Gand-20484...
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Adeline Gand, Mathias Antoine, Sandrine Boschi-Muller, Guy Branlant. Characterization of the Amino Acids Involved in Substrate Specificity of Methionine Sulfoxide Reductase A. Journal of Biological Chemistry, 2007, 282 (28), pp.20484-20491. ⟨10.1074/jbc.M702350200⟩. ⟨hal-01690658⟩



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