title: Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate.
abstract: Pyruvate dehydrogenase complex (PDHC) is a key enzyme in metabolism linking glycolysis to tricarboxylic acid cycle and its activity is tightly regulated by phosphorylation catalyzed by four pyruvate dehydrogenase kinase (PDK) isoforms. PDKs are pharmacological targets for several human diseases including cancer, diabetes, obesity, heart failure, and inherited PDHC deficiency. We investigated the inhibitory activity of phenylbutyrate toward PDKs and found that PDK isoforms 1-to-3 are inhibited whereas PDK4 is unaffected. Moreover, docking studies revealed putative binding sites of phenylbutyrate on PDK2 and 3 that are located on different sites compared to dichloroacetate (DCA), a previously known PDK inhibitor. Based on these findings, we showed both in cells and in mice that phenylbutyrate combined to DCA results in greater increase of PDHC activity compared to each drug alone. These results suggest that therapeutic efficacy can be enhanced by combination of drugs increasing PDHC enzyme activity.
authors.affiliation: Telethon Institute of Genetics and Medicine, Via Campi Felgrei, 34, 80078, Pozzuoli, Naples, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Ferriero
authors.forename: Clara
authors.initials: C
authors.lastname: Iannuzzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manco
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003999:Dichloroacetic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010654:Phenylbutyrates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000378:metabolism
chemical_list: C000631430:PDK2 protein, human; C000631432:PDK4 protein, human; C000631435:Pdk2 protein, mouse; C000631439:Pdk4 protein, mouse; D010654:Phenylbutyrates; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; C075773:4-phenylbutyric acid; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases