title: Diverse mechanisms of inhibition of pyruvate dehydrogenase kinase by structurally distinct inhibitors.
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.
authors.affiliation: Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901-1398, USA. william.mann@pharma.novartis.com
authors.forename: W R
authors.initials: WR
authors.lastname: Mann
authors.forename: C J
authors.initials: CJ
authors.lastname: Dragland
authors.forename: C C
authors.initials: CC
authors.lastname: Vinluan
authors.forename: T R
authors.initials: TR
authors.lastname: Vedananda
authors.forename: P A
authors.initials: PA
authors.lastname: Bell
authors.forename: T D
authors.initials: TD
authors.lastname: Aicher
mesh_terms: D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases