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Structural Basis for Flip-Flop Action of Thiamin Pyrophosphate-dependent Enzymes Revealed by Human Pyruvate DehydrogenaseThe derivative of vitamin B1, thiamin pyrophosphate, is a cofactor of enzymes performing catalysis in pathways of energy production. In alpha (sub 2) beta (sub 2)-heterotetrameric human pyruvate dehydrogenase, this cofactor is used to cleave the C(sup alpha) -C(=O) bond of pyruvate followed by reductive acetyl transfer to lipoyl-dihydrolipoamide acetyltransferase. The dynamic nonequivalence of two, otherwise chemically equivalent, catalytic sites has not yet been understood. To understand the mechanism of action of this enzyme, we determined the crystal structure of the holo-form of human pyruvate dehydrogenase at 1.95-Angstrom resolution. We propose a model for the flip-flop action of this enzyme through a concerted approximately 2-Angstrom shuttle-like motion of its heterodimers. Similarity of thiamin pyrophosphate binding in human pyruvate dehydrogenase with functionally related enzymes suggests that this newly defined shuttle-like motion of domains is common to the family of thiamin pyrophosphate-dependent enzymes.
Document ID
20040047251
Document Type
Reprint (Version printed in journal)
External Source(s)
Authors
Ciszak, Ewa M. (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
June 6, 2003
Publication Information
Publication: The Journal of Biological Chemistry
Volume: 278
Issue: 23
Subject Category
Inorganic, Organic and Physical Chemistry
Funding Number(s)
CONTRACT_GRANT: NAG8-1841
CONTRACT_GRANT: NIH-DK-20478
Distribution Limits
Public
Copyright
Other