title: Regulation of pyruvate dehydrogenase by insulin action.
abstract: In animal tissues the pyruvate dehydrogenase complex is regulated by product inhibition and by a phosphorylation-dephosphorylation cycle catalysed by a kinase and a phosphatase. Physiologic and molecular aspects of this regulation are reviewed, and the results of recent studies are described. Insulin deficiency in the rat (diabetes or starvation) is shown to inhibit the conversion of inactive (phospho-) complex into active (dephospho-) complex by the phosphatase by an effect on the substrate for the phosphatase (phosphorylated complex). This change is stable and persists during isolation, incubation, and extraction of mitochondria or purification of phosphorylated complex. The subunit ratios in the purified pig heart pyruvate dehydrogenase complex and the stoichiometry of phosphorylations have been determined by radioamidination and incorporation of 32P. The ratios of decarboxylase tetramer (alpha 2, beta 2) : dihydrolipoyl acetyltransferase monomer : dihydrolipoly dehydrogenase monomer were 1:1:0.5. Inactivation of the complex was accomplished by incorporation of a single phosphate into one alpha subunit of the decarboxylase tetramer. Two further phosphates are then incorporated and these additional phosphorylations inhibit reactivation of the complex by the phosphate. It is suggested that multisite phosphorylations may inhibit reactivation of the complex by the phosphatase in diabetes and in starvation.
mesh_terms: D000818:Animals; D002417:Cattle; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D066298:In Vitro Techniques; D007328:Insulin / Q000502:physiology*; D008929:Mitochondria, Heart / Q000201:enzymology; D010766:Phosphorylation; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051381:Rats; D013217:Starvation / Q000201:enzymology; D013552:Swine
chemical_list: D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase