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Structural Studies of Human Pyruvate DehydrogenaseHuman pyruvate dehydrogenase (E1) catalyzes the irreversible decarboxylation of pyruvate in the presence of Mg(2+) and thiamin pyrophosphate (TPP) followed by the rate-limiting reductive acetylation of the lipoyl moiety linked to dihydrolipoamide acetyltransferase. The three-dimensional structure of human E1 is elucidated using the methods of macromolecular X-ray crystallography. The structure is an alpha, alpha', beta and beta' tetramer with the protein units being in the tetrahedral arrangement. Each 361-residue alpha-subunit and 329-residue beta-subunit is composed of a beta-sheet core surrounded by alpha-helical domains. Each subunit is in extensive contact with all the three subunits involving TPP and magnesium cofactors, and potassium ions. The two binding sites for TPP are at the alpha-beta' and alpha'-beta interfaces, each involving a magnesium ion and Phe6l, His63, Tyr89, and Met200 from the alpha-subunit (or alpha'-subunit), and Met81 Phe85, His128 from the beta-subunit (or beta'-subunit). K+ ions are nestled between two beta-sheets and the end of an alpha-helix in each beta-subunit, where they are coordinated by four carbonyl oxygen groups from Ile12, Ala160, Asp163, and Asnl65, and a water molecule. The catalytic C2 carbon of thiazolium ring in this structure forms a 3.2 A contact with a water molecule involved in a series of H-bonds with other water molecules, and indirectly with amino acids including those involved in the catalysis and regulation of the enzyme.
Document ID
20020067638
Acquisition Source
Marshall Space Flight Center
Document Type
Conference Paper
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
(NASA Marshall Space Flight Center Huntsville, AL United States)
Sidhu, Sukhdeep
(State Univ. of New York Buffalo, NY United States)
Patel, Mulchand S.
(State Univ. of New York Buffalo, NY United States)
Curreri, Peter A.
Date Acquired
August 20, 2013
Publication Date
January 1, 2002
Subject Category
Aerospace Medicine
Meeting Information
Meeting: International Conference on Thiamin, Its Biochemistry and Structural Biology
Location: Newark, NJ
Country: United States
Start Date: May 18, 2002
End Date: May 21, 2002
Distribution Limits
Public
Copyright
Work of the US Gov. Public Use Permitted.

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