Pyruvate dehydrogenase kinase

Aicher, T.D., Anderson, R.C., Bebernitz, G.R.,ei al. (1999) (/ )-3,3,3-Trifluoro-2-hydroxy-2-methylpropiona-mides are orally active inhibitors of pyruvate dehydrogenase kinase. Journal of Medicinal Chemistry, 42, 2741-2746. 

Fig. 14.2. Regulation of the pyruvate dehydrogenase complex (PDC) from adult A suum muscle. PDC, pyruvate dehydrogenase complex E1, pyruvate dehydrogenase subunit of the PDC PDK, pyruvate dehydrogenase kinase PDP, pyruvate dehydrogenase phosphatase.

Chen, W., Huang, X., Komuniecki, P.R. and Komuniecki, R. (1998) Molecular cloning, functional expression, and characterization of pyruvate dehydrogenase kinase from anaerobic muscle of the parasitic nematode Ascaris suum. Archives of Biochemistry and Biophysics 353, 181-189. 

Rahmatullah, M. and Roche, T.E. (1985) Modification of bovine kidney pyruvate dehydrogenase kinase activity by CoA esters and their mechanism of action. Journal of Biological Chemistry 260, 10146—10152. 

Yang, D., Gong, X., Yakhnin, A. and Roche, T.E. (1998) Requirements for the adaptor protein role of dihydrolipoyl acetyltransferase in the up-regulated function of the pyruvate dehydrogenase kinase and pyruvate dehydrogenase phosphatase. Journal of Biological Chemistry 273, 14130-14137. 

PYRUVATE CARBOXYLASE PYRUVATE DEHYDROGENASE KINASE PYRUVATE KINASE PYRUVATE, WATER DIKINASE RESTRICTION ENZYMES RHODOPSIN KINASE RIBOFLAVIN KINASE RIBONUCLEOTIDE REDUCTASE... 

PYRUVATE CARBOXYLASE PYRUVATE DECARBOXYLA.se PYRUVATE DEHYDROGENASE PYRUVATE DEHYDROGENASE KINASE... 

Regulation of the Pyruvate Dehydrogenase Complex In animal tissues, the rate of conversion of pyruvate to acetyl-CoA is regulated by the ratio of active, phosphory-lated to inactive, unphosphorylated PDH complex. Determine what happens to the rate of this reaction when a preparation of rabbit muscle mitochondria containing the PDH complex is treated with (a) pyruvate dehydrogenase kinase, ATP, and NADH (b) pyruvate dehydrogenase phosphatase and Ca2+ (c) malonate. 

The regulatory role of calcium ions in intermediary metabolism is well documented. Calcium has been shown to be involved in activation or inhibition of specific enzyme systems [105], For example, it activates cyclic nucleotide phosphodiesterase, phosphofructokinase, fructose 1 6 biphosphatase, glycerol phosphate dehydrogenase, pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase. Calcium ions inhibit pyruvate kinase, pyruvate carboxylase, Na+/K+-AT-Pase and adenylate cyclase. 

DCA is an inhibitor of pyruvate dehydrogenase kinase, the enzyme that regulates pyruvate dehydrogenase (PDH) activity by phosphorylation of the Ex subunit, leading to a decrease in PDH activity (see Chapter 7). DCA has been used to lower lactate levels in some patients with MELAS. Stimulation of PDH activity reduces the release of lactate from peripheral tissues and enhances its metabolism by the liver. Since prolonged use of DCA may lead to sensory neuropathy, treatment must be closely monitored. 

Control of the activity of the pyruvate dehydrogenase complex is exerted by the phosphorylation of pyruvate decarboxylase (E[), which renders it inactive. This process is catalyzed by pyruvate dehydrogenase kinase, which is always tightly bound to E[. The kinase is activated by high-energy conditions, and it requires ATP to accomplish the phosphorylation step. Another enzyme, phosphoprotein phosphatase, is weakly bound to E, and reactivates the system by removing the inhibitory phosphate group (Fig. 12-8). 

Pyruvate dehydrogenase kinases are induced by glucocorticoid hormones and long-chain fatty acids (acting via the peroxisome proliferation-activated... 

Hnang B, Wn P, Bowker-Kinley MM, and Harris RA (2002) Regnlation of pyruvate dehydrogenase kinase expression hy peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes 51,276-83. 

Sugden MC, Bulmer K, Augustine D, and Holness MJ (2001a) Selective modification of pyruvate dehydrogenase kinase isoform expression in rat pancreatic islets elicited by starvation and activation of peroxisome proliferator-activated receptor-alpha implications for glucose-stimulated insulin secretion. Diabetes 50, 2729-36. 

Korotchkina LG and Patel MS (2001b) Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase./owmal of Biological Chemistry 276, 37223-9. 

Metabolic intermediates and other local" effectors Many target specific enzymes, such as pyruvate dehydrogenase kinase and branched-chain ketoacid dehydrogenase kinase ... 

M. Bowker-Kinley and K.M. Popov. 1999. Evidence that pyruvate dehydrogenase kinase belongs to the ATPase/kinase superfamily Biochem. J. 1 47-53. 

An analogue of pyruvate, dichloroacetate (CHCl2COO ), inhibits pyruvate dehydrogenase kinase and maintains the pyruvate dehydrogenase complex... 

Hiromasa, Y.. and Roche, T. E. 2003. Facilitated interaction between the pyruvate dehydrogenase kinase isulorin 2 and the dihydrolipoyl acetyltransferases./. Biol. Chem. 278 33681 33693. 

---