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Structural Model for the Flip-Flop Action in Thiamin Pyrophosphate-Dependent Human Pyruvate DehydrogenaseThe derivative of vitamin B1 thiamin pyrophosphate (TPP) is a cofactor of enzymes performing catalysis in pathways of energy production, including (i) decarboxylation of alpha-keto acids followed by (ii) transketolation. These enzymes have shown a common mechanism of TPP activation by imposing an active V-conformation of this coenzyme that brings the N4 atom of the aminopyrimidine ring to the distance required for the intramolecular C-H N hydrogen-bonding with the C2- atom of the thiazolium ring. The reactive C2 atom of TPP is the nucleophile that attacks the carbonyl carbon of different substrates used by the TPP-dependent enzymes. The structure of the heterotetrameric human pyruvate dehydrogenase (Elp) recently determined in our laboratory (1) revealed the association pattern of the subunits and the specifics of two chemically equivalent cofactor binding sites. Dynamic nonequivalence of these two cofactor sites directs the flip-flop action of this enzyme, depending upon which two active sites effect each other (2). The crystal structure derived from the holo-form of Elp provided the basis for the model of the flip-flop action of Elp in which different steps of the catalytic reaction are performed in each of the two cofactor sites at any given moment, where these steps are governed by the concerted shuttle-like motion of the subunits. It is further proposed that balancing a hydrogen-bond network and related cofactor geometry determine the continuity of catalytic events.
Document ID
20030066373
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
Energy Production and Conversion
Meeting Information
Gordon Research Conference(Meriden, NH)
Distribution Limits
Public
Copyright
Other