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Etude originale par diffraction des rayons X d'une aldéhyde déshydrogénase non-phosphorylante, décarboxylante et CoenzymeA-dépendante : la méthylmalonate semialdéhyde deshydrogénase de Bacillus subtilis

Abstract : The methylmalonate semialdehyde dehydrogenase (MSDH) catalyses the oxidation of methylmalonate semialdehyde (MMSA) and malonate semialdehyde (MSA) into propionyl-CoA and acetyl-CoA, respectively. MSDH is a particular member of the non-phosphorylating and NAD(P)+-dependent aldehyde dehydrogenase family (ALDHs). Indeed, this is a decarboxylating, NAD+ and CoA-dependent enzyme which functions via a three-step mechanism. The first step, in which the acylenzyme and the NADH are produced, is common to that of other ALDHs. The second and third steps consist of a b-decarboxylation and a deacylation processes. This thesis covers the work of determining crystallographic structures of the MSDH of Bacillus subtilis (Bs_MSDH) in complex with its substrates, in order to reveal the essential structural elements, important for the enzymatic mechanism. Globally, the structure of Bs_MSDH is comparable to that of those tetrameric ALDHs. The diffusion of a racemic mixture of MMSA in the Bs_MSDH/NAD+ complex crystals allows us in obtaining the reactional intermediate acylenzyme structure where stereoisomer S-MMSA is covalently bound to the enzyme and is not b-decarboxylated. These results are consistent with a ping-pong type mechanism where the NADH is released before the decarboxylation and the binding of CoA. The structures of the complexes with CoA highlight a signature sequence of xPxP aminocyls, a characteristic of the CoA-fixation in CoA-dependent ALDHs. This signature sequence is the principal hook-on point of CoA in the funnel of the MSDH active site.
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Hélène Dubourg-Gerecke. Etude originale par diffraction des rayons X d'une aldéhyde déshydrogénase non-phosphorylante, décarboxylante et CoenzymeA-dépendante : la méthylmalonate semialdéhyde deshydrogénase de Bacillus subtilis. Biochimie, Biologie Moléculaire. Université Henri Poincaré - Nancy 1, 2006. Français. ⟨NNT : 2006NAN10128⟩. ⟨tel-01748188⟩

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