Sep 27, 2000

Diverse mechanisms of inhibition of pyruvate dehydrogenase kinase by structurally distinct inhibitors

Biochimica Et Biophysica Acta
W R MannT D Aicher

Abstract

The mechanism of action of structurally distinct pyruvate dehydrogenase kinase (PDK) inhibitors was examined in assays with experimental contexts ranging from an intact pyruvate dehydrogenase complex (PDC) with and without supplemental ATP or ADP to a synthetic peptide substrate to PDK autophosphorylation. Some compounds directly inhibited the catalytic activity of PDKs. Some of the inhibitor classes tested inhibited autophosphorylation of recombinant PDK1 and PDK2. During these studies, PDC was shown to be directly inhibited by a novel mechanism; the addition of supplemental recombinant PDKs, an effect that is ADP-dependent and partly alleviated by members of each of the compound classes tested. Overall, these data demonstrate that small molecules acting at diverse sites can inhibit PDK activity.

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Citations

Mentioned in this Paper

Protein Kinase Inhibitors
SDS-PAGE
PDK1
Protein KINASE
Enzyme Inhibitors
Pyruvate dehydrogenase kinase isoform 4
PDK2
Protein-Serine-Threonine Kinases
Phosphorylation

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