Topic
Pyruvate dehydrogenase kinase
About: Pyruvate dehydrogenase kinase is a research topic. Over the lifetime, 4224 publications have been published within this topic receiving 161052 citations. The topic is also known as: [pyruvate dehydrogenase (lipoamide)] kinase & pyruvate dehydrogenase (lipoamide) kinase.
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TL;DR: Results suggest that overexpression of HIF-2α in CCRCC 786-0 tumors regulated growth both by maintaining a low level of glycolysis and by allowing more mitochondrial metabolism and tolerance to ROS induced DNA damage.
Abstract: In cultured clear-cell renal carcinoma (CCRCC) 786-0 cells transfected with HIF1alpha (HIF-1+), HIF-2alpha (HIF-2+), or empty vector (EV), no significant differences were observed in the growth rates in vitro, but when grown in vivo as xenografts HIF-2alpha significantly increased, and HIF-1alpha significantly decreased growth rates, compared to EV tumors. Factors associated with proliferation were increased and factors associated with cell death were decreased in HIF-2+ tumors. Metabolite profiles showed higher glucose and lower lactate and alanine levels in the HIF-2+ tumors whilst immunostaining demonstrated higher pyruvate dehydrogenase and lower pyruvate dehydrogenase kinase 1, compared to control tumors. Taken together, these results suggest that overexpression of HIF-2alpha in CCRCC 786-0 tumors regulated growth both by maintaining a low level of glycolysis and by allowing more mitochondrial metabolism and tolerance to ROS induced DNA damage. The growth profiles observed may be mediated by adaptive changes to a more oxidative phenotype.
80 citations
TL;DR: Methyl substitution of the piperazine at the 2- and 5-positions markedly increased the potency of the lead compound (>1,000-fold) and oral bioavailability of the compounds in this series is good and is optimal when the 4-position of thepiperazine is substituted with an electron-poor benzoyl moiety.
Abstract: N‘-Methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC50 = 180 μM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S,R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibi...
80 citations
TL;DR: Evidence is described indicating that the alterations in glucose metabolism in hypertrophied hearts cannot be explained simply by changes in PDC expression or control, and mechanisms that may lead to an altered balance of pyruvate metabolism in cardiac hypertrophy are discussed.
Abstract: Cardiac hypertrophy, induced by chronic pressure or volume overload, is associated with abnormalities in energy metabolism as well as characteristic increases in muscle mass and alterations in the structure of the heart. Hypertrophied hearts display increased rates of glycolysis and overall glucose utilization, but rates of pyruvate oxidation do not rise in step with rates of pyruvate generation. Glycolysis and glucose oxidation, therefore, become markedly less 'coupled' in hypertrophied hearts than in non-hypertrophied hearts. Because the pyruvate dehydrogenase complex (PDC) contributes so powerfully to the control of glucose oxidation, we set out to test the hypothesis that the function of PDC is impaired in cardiac hypertrophy. In this review we describe evidence indicating that the alterations in glucose metabolism in hypertrophied hearts cannot be explained simply by changes in PDC expression or control. Additional mechanisms that may lead to an altered balance of pyruvate metabolism in cardiac hypertrophy are discussed, with commentaries on possible changes in pyruvate transport, NADH shuttles, lactate dehydrogenase, and amino acid metabolism.
79 citations
TL;DR: In vitro protein synthesis experiments using RNA extracted from rat red cells and liver are described which demonstrate that the difference is reflected in tissue-specific mRNAs and is not due to post-translational processing.
Abstract: Pyruvate kinase subunits of red cells and liver differ in their molecular weights. Peptide mapping of the rat enzymes has shown that this difference is due to a single exon peptide present in the red cell enzyme1‐3. There is strong genetic evidence in man that both enzymes are encoded by the same structural gene (refs 4–8 and G. E. J. Staal et al., personal communication). Here we describe in vitro protein synthesis experiments using RNA extracted from rat red cells and liver which demonstrate that the difference is reflected in tissue-specific mRNAs. Thus the difference is not due to post-translational processing and presumably involves either gene rearrangement or differential processing of a common nuclear RNA precursor.
79 citations
TL;DR: Responses to the adenylate energy charge, the DPN+ mole fraction, and the acetyl coenzyme A concentration are in the right direction and the interactions are of the right type, to suggest that modulation of pyruvate dehydrogenase activity contributes to the stabilization of these parameters in vivo.
79 citations