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Structural Basis for Flip-Flop Action of Thiamin-Dependent Enzymes Revealed by Crystal Structure of Human Pyruvate DehydrogenaseThe biologically active derivative of vitamin B1; thiamin pyrophosphate; is used as cofactor by many enzymes that perform a wide range of catalytic functions in the pathways of energy production. In alpha2beta2-heterotetrameric human pyruvate dehydrogenase, the first catalytic component enzyme of human pyruvate dehydrogenase complex, this cofactor is used to cleave the C(sup alpha)-C(=0) bond of pyruvate followed by reductive acetyl transfer to lipoyl-dihydrolipoamide acetyltransferase, the second catalytic component of the complex. The dynamic nonequivalence of two, otherwise chemically equivalent, catalytic sites have puzzled researchers from earlier functional studies of this enzyme. In order to gain insight into the mechanism of action of this enzyme, we determined the crystal structure of the holoform of human pyruvate dehydrogenase at 1.958, resolution. We propose a kinetic model for the flip-flop action of this enzyme through the concerted approx. 2A, shuttle-like motion of the heterodimers. The similarity of thiamin pyrophosphate binding in human pyruvate dehydrogenase and other functionally related enzymes suggests this newly defined mechanism of shuttle-like motion of domains to be common for the family of thiamin pyrophosphate-dependent enzymes.
Document ID
20030062117
Acquisition Source
Marshall Space Flight Center
Document Type
Preprint (Draft being sent to journal)
Authors
Ciszak, Ewa
(NASA Marshall Space Flight Center Huntsville, AL, United States)
Korotchkina, Lioubov G.
(State Univ. of New York Buffalo, NY, United States)
Dominiak, Paulina M.
(NASA Marshall Space Flight Center Huntsville, AL, United States)
Sidhu, Sukdeep
(State Univ. of New York Buffalo, NY, United States)
Patel, Mulchand S.
(State Univ. of New York Buffalo, NY, United States)
Date Acquired
August 21, 2013
Publication Date
January 1, 2003
Subject Category
Solid-State Physics
Distribution Limits
Public
Copyright
Other

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