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Structure-Derived Proton-Transfer Mechanism of Action Human Pyruvate DehydrogenaseThe derivative of vitamin B1 thiamin pyrophosphate (TPP) is a cofactor of pyruvate dehydrogenase (E1p) that is involved in decarboxylation of pyruvate followed by reductive acetylation of lipoic acid covalently bound to a lysine residue of dihydrolipoamide acetyltransferase. The structure of E1p recently determined in our laboratory revealed patterns of association of foul subunits and specifics of two TPP binding sites. The mechanism of action in part includes a conserved hydrogen bond between the N1' atom of the aminopyrimidine ring of the cofactor and the carboxylate group of Glu59 from the beta subunits, and a V-conformation of the cofactor that brings the N4' atom of the aminopyrimidine ring to the distance of the intramolecular hydrogen bond formed with the C2-atom of the thiazolium moiety. The carboxylate group of Glu59 is the local proton acceptor that enables proton translocation within the aminopyrimidine ring and stabilization of the rare N4' - iminopyrimidine tautomer. Based on the analysis of E1p structure, we postulate that the protein environment drives N4' - amino/N4' - imino dynamics resulting in a concerted shuttle-like movement of the subunits. We also propose that this movement of the subunits is strictly coordinated with the two enzymatic reactions carried out in E1p by each of the two cofactor sites. It is proposed that these reactions are in alternating phases such that when one active site is involved in decarboxylation, the other is involved in acetylation of lipoyl noiety.
Document ID
20030067925
Acquisition Source
Marshall Space Flight Center
Document Type
Conference Paper
Authors
Ciszak, Ewa
(NASA Marshall Space Flight Center Huntsville, AL, United States)
Dominiak, Paulina
(NASA Marshall Space Flight Center Huntsville, AL, United States)
Date Acquired
August 21, 2013
Publication Date
January 1, 2003
Subject Category
Life Sciences (General)
Distribution Limits
Public
Copyright
Work of the US Gov. Public Use Permitted.

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