Regulation of the pyruvate dehydrogenase and branched chain alpha-ketoacid dehydrogenase complexes by covalent modification
Characterization of the mitochondrial protein kinases and phosphatases
Regulation of the expression of pyruvate dehydrogenase kinase 4
Characterization of PDK and BDK knockout mice
Assay of the pyruvate dehydrogenase and branched chain keto acid dehydrogenase complex
Regulation of mitochondrial kinases and phosphatases; regulation of gene expression
The activity of the pyruvate dehydrogenase complex (PDC) is regulated by interconversion of phosphorylated (inactive) and non-phosphorylated (active) forms of the complex. Phosphorylation is catalyzed by four pyruvate dehydrogenase kinase (PDK) isoenzymes; dephosphorylation by two pyruvate dehydrogenase phosphatase (PDP) isoenzymes. Unique regulatory properties of these isoenzymes and differences in their levels of expression in different cell types provide tissue specific control of the activity of PDC. Current work is based on our recent finding that one of the PDK isoenzymes, PDK4, is markedly increased in the tissues of insulin-deficient rats. We propose that altered expression of this PDK isoenzyme is an important component of the regulatory mechanisms triggered by insulin deficiency to conserve glucose and the three-carbon compounds required for glucose synthesis. Our working hypothesis is that alterations in the expression of the genes encoding the PDK isoenzymes are responsible for the hyperphosphorylation and therefore inactivation of PDC in metabolically important tissues during insulin deficiency. The hypothesis is being tested by: (a) quantifying the changes that occur in expression of the PDK isoenzymes in metabolically important tissues in insulin deficient and resistant states, (b) identifying the physiologically important factors that regulate PDK4 expression, and (c) determining the molecular mechanism responsible for the large increase in ,message level of PDK4 that occurs in tissues in response to insulin deficiency. We believe the findings of this study will provide new insight with respect to a regulatory mechanism crucial for glucose homeostasis. It will also contribute to our understanding of why consumption of the typical Western diet inappropriately spares carbohydrate from oxidation and promotes the development of type 2 diabetes. Regulation of the pyruvate dehydrogenase and branched chain alpha-ketoacid dehydrogenase complexes by covalent modification
Characterization of the mitochondrial protein kinases and phosphatases
Regulation of the expression of pyruvate dehydrogenase kinase 4
Characterization of PDK and BDK knockout mice
Assay of the pyruvate dehydrogenase and branched chain keto acid dehydrogenase complex
Regulation of carbohydrate, protein, and lipid metabolism Biochemistry, Biochemistry, Carbohydrates, Diabetes, Enzymes, Enzymology, Inhibitors, Metabolic Diseases, Metabolism, Metabolism, Amino Acid, Metabolism, Lipid, Metabolism, Protein, Nutrition/Dietetics, Obesity One of our working hypotheses is that pyruvate dehydrogenase kinases are targets for the treatment of type 2 diabetes.
Another is the idea that regulation of the branched chain alpha ketoacid dehydrognease kinase may prove useful in the promotion of muscle acretion and growth. Role of 3-hydroxyisobutyryl-CoA hydrolase in the hydrolysis of methylmalonyl-CoA in vitamin B12 deficiency
Production of transgenic mice that over express branched chain alpha ketoacid dehydrogenase kinase
