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Etude structurale et fonctionnelle de la Quinolinate Synthase : une protéine fer-soufre cible d'agents antibactériens

Abstract : Quinolinate synthase (NadA) catalyses a unique condensation reaction between iminoaspartate and dihydroxacetone phosphate leading to quinolinic acid, a key intermediate in the biosynthesis of nicotinamide adenine dinucleotide (NAD). This study demonstrates that all quinolinate synthases harbor a [4Fe-4S] cluster, absolutely required for activity, which is coordinated by only three cysteine residues, namely the conserved Cys113, Cys200 and Cys297 in NadA from E. coli. Spectroscopic and biochemical properties of [4Fe-4S] clusters lead to the proposal that the iron-sulfur cluster plays an aconitase/dehydratase-type role in this enzymatic catalysis. Two other cysteine residues (Cys291 and Cys294 in E. coli) were demonstrated to be involved in the formation of a disulfide bridge critical for the quinolinate synthase activity probably by playing a regulatory role. In this work we also propose an additional step in the mechanism including the isomerisation of glyceraldehyde 3-phosphate (G-3P) to DHAP. Finally, some putative inhibitory molecules were assayed on NadA that we consider as a potential target of antibacterial agents. Among the tested molecules, phosphoglycolohydroxamic acid (PGH), proves to be active on the quinolinate synthases of E. coli and M. tuberculosis, acting as a competitive inhibitor of DHAP.
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https://tel.archives-ouvertes.fr/tel-00576109
Contributor : Carine Rousset <>
Submitted on : Saturday, March 12, 2011 - 1:31:02 PM
Last modification on : Tuesday, July 27, 2021 - 10:28:02 AM
Long-term archiving on: : Monday, June 13, 2011 - 2:20:11 AM

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Carine Rousset. Etude structurale et fonctionnelle de la Quinolinate Synthase : une protéine fer-soufre cible d'agents antibactériens. Biochimie [q-bio.BM]. Université Joseph-Fourier - Grenoble I, 2009. Français. ⟨tel-00576109⟩

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