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Structural Basis for "Flip-Flop" Action of Human Pyruvate DehydrogenaseThe derivative of vitamin B1, thiamin pyrophosphate is a cofactor of pyruvate dehydrogenase, a component enzyme of the mitochondrial pyruvate dehydrogenase multienzyme complex that plays a major role in directing energy metabolism in the cell. This cofactor is used to cleave the C(sup alpha)-C(=O) bond of pyruvate followed by reductive acetyl transfer to lipoyl-dihydrolipoamide acetyltransferase. In alpha(sub 2)beta(sub 2)-tetrameric human pyruvate dehydrogenase, there are two cofactor binding sites, each of them being a center of independently conducted, although highly coordinated enzymatic reactions. The dynamic nonequivalence of two, otherwise chemically equivalent, catalytic sites can now be understood based on the recently determined crystal structure of the holo-form of human pyruvate dehydrogenase at 1.95A resolution. The structure of pyruvate dehydrogenase was determined using a combination of MAD phasing and molecular replacement followed by rounds of torsion-angles molecular-dynamics simulated-annealing refinement. The final pyruvate dehydrogenase structure included coordinates for all protein amino acids two cofactor molecules, two magnesium and two potassium ions, and 742 water molecules. The structure was refined to R = 0.202 and R(sub free) = 0.244. Our structural analysis of the enzyme folding and domain assembly identified a simple mechanism of this protein motion required for the conduct of catalytic action.
Document ID
20030065838
Acquisition Source
Marshall Space Flight Center
Document Type
Conference Paper
Authors
Ciszak, Ewa
(Alabama Univ. Huntsville, AL, United States)
Korotchkina, Lioubov
(State Univ. of New York at Buffalo Buffalo, NY, United States)
Dominiak, Paulina
(NASA Marshall Space Flight Center Huntsville, AL, United States)
Sidhu, Sukhdeep
(State Univ. of New York at Buffalo Buffalo, NY, United States)
Patel, Mulchand
(State Univ. of New York at Buffalo Buffalo, NY, United States)
Date Acquired
August 21, 2013
Publication Date
January 1, 2003
Subject Category
Inorganic, Organic And Physical Chemistry
Meeting Information
Meeting: American Crystallographic Association Meeting
Location: Cincinnati, OH
Country: United States
Start Date: July 26, 2003
End Date: July 31, 2003
Sponsors: American Crystallographic Association
Distribution Limits
Public
Copyright
Other

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