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Targeting the sub‐domains of Acetyl‐coenzyme A Carboxlyase for Drug Development: Kinetic confirmation of compound MOA on half‐reactions.
Author(s) -
Olson Matthew Wayne,
SchalkHihi Celine,
Dzordzorme Keli,
Gaul Mike,
Baindur Nand,
Xiang Min,
Kuo Gee Hong,
Sun Wenfeng,
Kirkpatrick Jennifer,
Baumann Christian,
Lenhard James,
Nelen Marina,
Nulton Erica,
Singleton Kenneth,
Steele Ruth,
Kuo Lawrence,
Matthew Todd J.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.332
Subject(s) - carboxylation , cofactor , chemistry , biotin , coenzyme a , enzyme , acetyl coa , covalent bond , biochemistry , fatty acid , fatty acid synthesis , beta oxidation , metabolism , catalysis , stereochemistry , organic chemistry , reductase
Acetyl‐coenzyme A Carboxlyase (ACC) is a large multi‐domain enzyme in eukaryotes that is responsible for the catalysis of acetyl‐CoA to malonyl‐CoA, a crucial step in fatty acid metabolism. A study of ACC2 −/−‐ mice showed a dramatic reduction in malonyl‐CoA levels in heart and skeletal muscle (1); these animals displayed continuous fatty acid oxidation, reduced fat mass and body weight. The enzyme mechanism of ACC requires the oscillation of a covalently bound biotin cofactor between domains catalyzing the two half‐reactions: 1) Biotin carboxylation, whereby ATP‐dependent carboxylation is used to fix CO 2 onto covalently attached biotin; 2) Carboxyltransferase (CT), where the carboxyl group (from the activated carboxylated biotin) is transferred to the methyl group on acetyl‐CoA generating malonyl‐CoA that is subsequently liberated. Kinetics of ACC activity were monitored by HT‐LC/MS, quantitatively monitoring all substrates and products. We report herein the evaluation of two compounds (of dissimilar structure) that affect acetyl‐CoA carboxylation by inhibiting alternate half‐reactions.