Structural determination and kinetic analysis of the Transketolase from Vibrio vulnificus reveal unexpected cooperative behavior - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Protein Science Année : 2023

Structural determination and kinetic analysis of the Transketolase from Vibrio vulnificus reveal unexpected cooperative behavior

Résumé

Vibrio vulnificus (vv) is a multidrug-resistant human bacterial pathogen whose prevalence is expected to increase over the years. Transketolases (TK), transferases catalyzing two reactions of the non-oxidative branch of the pentose-phosphate pathway and therefore linked to several crucial metabolic pathways, are potential targets for new drugs against this pathogen. Here, the vvTK is crystallized and its structure is solved at 2.1 Å. A crown of 6 histidyl residues is observed in the active site and expected to participate in the thiamine pyrophosphate (cofactor) activation. Docking of fructose-6-phosphate and ferricyanide used in the activity assay, suggests that both substrates can bind vvTK simultaneously. This is confirmed by steady-state kinetics showing a sequential mechanism, on the contrary to the natural transferase reaction which follows a substituted mechanism. Inhibition by the I38-49 inhibitor (2-(4-ethoxyphenyl)-1-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine) reveals for the first time a cooperative behavior of a TK and docking experiments suggest a previously undescribed binding site at the interface between the pyrophosphate and pyridinium domains.
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hal-04409850 , version 1 (22-01-2024)

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Rainier-Numa Georges, Lionel Ballut, Guillaume Octobre, Arnaud Comte, Laurence Hecquet, et al.. Structural determination and kinetic analysis of the Transketolase from Vibrio vulnificus reveal unexpected cooperative behavior. Protein Science, In press, ⟨10.1002/pro.4884⟩. ⟨hal-04409850⟩
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