Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.2 (PDK1)
2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of severe insulin-induced hypoglycemia on the activity of the pyruvate dehydrogenase enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex during burst suppression EEG, after 10, 30, and 60 min of isoelectric EEG, and after 30 and 180 min and 24 h of recovery following 30 min of hypoglycemic coma. Changes in PDHC activity were correlated to levels of labile organic phosphates and glycolytic metabolites. In cortex from control animals, the rate of [1-14C]pyruvate decarboxylation was 7.1 +/- 1.3 U/mg of protein, or 35% of the total PDHC activity. The activity was unchanged during burst suppression EEG whereas the active fraction increased to 81-87% during hypoglycemic coma. Thirty minutes after glucose-induced recovery, the PDHC activity had decreased by 33% compared to control levels, and remained significantly depressed after 3 h of recovery. This decrease in activity was not due to a decrease in the total PDHC activity. At 24 h of recovery, PDHC activity had returned to control levels. We conclude that the activation of PDHC during hypoglycemic coma is probably the result of an increased PDH phosphatase activity following depolarization and calcium influx, and allosteric inhibition of PDH kinase due to increased ADP/ATP ratio. The depression of PDHC activity following hypoglycemic coma is probably due to an increased phosphorylation of the enzyme, as a consequence of an imbalance between PDH phosphatase and kinase activities. Since some reduction of the ATP/ADP ratio persisted and since the lactate/pyruvate ratio had normalized by 3 h of recovery, the depression of PDHC most likely reflects a decrease in PDH phosphatase activity, probably due to a decrease in intramitochondrial Ca2+.
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PMID:Changes in pyruvate dehydrogenase complex activity during and following severe insulin-induced hypoglycemia. 198 96

We have previously shown that normal Wistar rats fed for 3 weeks with an isocaloric sucrose-rich (63%) diet (SRD) develop high levels of plasma free fatty acids and increased triacylglycerol content in the myocardium. We are now reporting that these changes are accompanied by remarkably low levels of the active form of the pyruvate dehydrogenase complex (PDHa; mean +/- SEM, 37.2% +/- 3.7% of the total activity) when compared with levels found in hearts donated by control rats fed the standard chow diet (STD; 71.0% +/- 2.8%; P less than .01). Increased concentrations of both long-chain acyl-CoA (0.21 +/- 0.03 v 0.06 +/- 0.01 mumol.g dry weight-1 found in STD; P less than .01) and acetyl-CoA (0.17 +/- 0.05 v 0.09 +/- 0.01 found in STD; P less than .01), as well as a relative decrease in coenzyme A (CoASH) (0.21 +/- 0.02 v 0.32 +/- 0.05 from STD; P = NS), resulting in an increased acetyl-CoA/CoASH ratio (0.80 +/- 0.13 v 0.29 +/- 0.03 in STD; P less than .01) may have stimulated the PDH kinase, leading in turn to an inactivation of the PDH complex. The above enzymatic and metabolic changes in the in situ heart of SRD-fed rats were still present after perfusing them for 35 minutes with a Krebs-Henseleit buffer containing 11 mmol/L glucose as the only exogenous substrate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biochemical abnormalities in the heart of rats fed a sucrose-rich diet: is the low activity of the pyruvate dehydrogenase complex a result of increased fatty acid oxidation? 198 63

The effect of sterile inflammation and sepsis on the proportion of active pyruvate dehydrogenase complex (PDH) in mitochondria isolated from skeletal muscle has been investigated. The proportion of active PDH in mitochondria isolated from septic animals was significantly reduced compared with control under all incubation conditions examined, even in the presence of inhibitors of the PDH kinase. There was no significant difference between control and sterile inflammation in any of the incubations examined. The rate constant for ATP-dependent inactivation of the PDH complex in mitochondrial extracts from control animals was -0.42 min-1 (r = 0.993; P less than 0.001) and was not altered in mitochondrial extracts from sterile inflammatory animals (-0.43 min-1; r = 0.999; P less than 0.001). However, rate constants for inactivation in septic animals was significantly increased over twofold to -1.08 min-1 (r = 0.987; P less than 0.001) (P less than 0.001 vs. control or sterile inflammation). In the presence of inhibitors of the PDH kinase reaction (2.5 mM pyruvate or 1 mM dichloroacetate), inactivation of PDH after addition of ATP was significantly greater in mitochondrial extracts from septic than either control or sterile inflammatory animals. These results suggest that sepsis, but not sterile inflammation, induces a stable factor in skeletal muscle mitochondria that increased PDH kinase activity.
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PMID:Increased pyruvate dehydrogenase kinase activity in response to sepsis. 203 22

It is shown here that rat liver pyruvate dehydrogenase (PDH) kinase activator protein (KAP) catalyses ATP-dependent inactivation and [32P]phosphorylation of pig heart PDHE1 and of yeast (Saccharomyces cerevisiae) PDH complex devoid of PDH kinase activity, that fluorosulphonylbenzoyladenosine inactivates rat liver KAP and the intrinsic PDH kinase of rat liver PDH complex, and that KAP, like PDH kinase, is inactivated by thiol-reactive reagents. It is concluded that KAP is a free PDH kinase.
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PMID:Evidence that rat liver pyruvate dehydrogenase kinase activator protein is a pyruvate dehydrogenase kinase. 203 54

Dichloroacetate (DCA) activates pyruvate dehydrogenase (PDH) by inhibiting PDH kinase. Neutralized DCA (100 mg/kg) or saline was intravenously administered to 20 to 25-day-old rats (50-75g). Fifteen minutes later a mixture of [6-14C]glucose and [3H]fluorodeoxyglucose (FDG) was administered intravenously and the animals were sacrificed by microwave irradiation (2450 MHz, 8.0 kW, 0.6-0.8 sec) after 2 or 5 min. Brain regional rates of glucose use and metabolite levels were determined. DCA-treated rats had increased rates of glucose use in all regions studied (cortex, thalamus, striatum, and brain stem), with an average increase of 41%. Lactate levels were lower in all regions, by an average of 35%. There were no significant changes in levels of ATP, creatine phosphate, or glycogen in any brain region. Blood levels of lactate did not differ significantly between the DCA- and the saline-treated groups. Blood glucose levels were higher in the DCA group. In rats sacrificed by freeze-blowing, DCA treatment caused lower brain levels of both lactate and pyruvate. These results cannot be explained by any systemic effect of DCA. Rather, it appears that in the immature rat, DCA treatment results in activation of brain PDH, increased metabolism of brain pyruvate and lactate, and a resulting increase in brain glycolytic rate.
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PMID:Dichloroacetate increases glucose use and decreases lactate in developing rat brain. 208 18

The activity of pyruvate dehydrogenase (PDH) complex and PDH kinase were measured in brown adipose tissue (BAT) of 4-week-gold thioglucose (GTG)-obese mice. The proportion of PDH complex in the active dephosphorylated form was 2-fold higher in BAT of post-absorptive obese mice compared with lean controls. This result was consistent with the higher circulating insulin concentration observed in GTG-obese mice. In both obese and lean mice the PDH-complex activity in BAT decreased after 24 h starvation and increased in response to supraphysiological insulin injection, indicating that the PDH complex is insulin-responsive in BAT of GTG-obese mice. There was no difference in the PDH kinase activity of BAT in post-absorptive or insulin-injected lean and obese mice, suggesting that the higher PDH-complex activity in obese mice was not due to decreased PDH kinase activity. There is no evidence for a decreased activity of PDH complex contributing to insulin resistance in BAT of 4-week-GTG-obese mice.
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PMID:Pyruvate dehydrogenase-complex activity in brown adipose tissue of gold thioglucose-obese mice. 211 59

The increased activity of pyruvate dehydrogenase (PDH) kinase induced in hearts of rats by starvation for 48 h was maintained following preparation of cardiac myocytes, and it was also maintained, though at a decreased level, after 25 h of culture in medium 199. This loss of PDH kinase activity was not prevented by n-octanoate, dibutyryl cyclic AMP or glucagon. The PDH kinase activity of myocytes from fed rats was increased to that of starved rats after 25 h of culture with n-octanoate, dibutyryl cyclic AMP or both agents together.
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PMID:Longer-term regulation of pyruvate dehydrogenase kinase in cultured rat cardiac myocytes. 215 9

Purified bovine heart pyruvate dehydrogenase complex was used to investigate the effects of monovalent cations and alpha-ketoisovalerate on pyruvate dehydrogenase (PDH) kinase inhibition by thiamin pyrophosphate. Initial velocity patterns for thiamin pyrophosphate inhibition were consistent with hyperbolic non-competitive or hyperbolic uncompetitive inhibition at various K+ concentrations between 0 and 120 mM. The Kis, Kid, and Kin for thiamin pyrophosphate were in the range of 0.009 to 5.1 microM over the range of K+ concentrations tested. In the absence of K+, 1 mM alpha-ketoisovalerate had no effect on PDH kinase inhibition by thiamin pyrophosphate, whereas in the presence of 20 mM K+, alpha-ketoisovalerate stimulated PDH kinase activity almost 2-fold over the range of 0-80 microM thiamin pyrophosphate. Half-maximal stimulation by alpha-ketoisovalerate occurred at about 200 microM in the presence of 100 microM thiamin pyrophosphate and 20 mM K+. Similar but less extensive changes occurred in the presence of 100 microM thiamin pyrophosphate and 1 mM NH4+. Initial velocity patterns for PDH kinase inhibition by thiamin pyrophosphate in the presence of 2 mM alpha-ketoisovalerate were mixed noncompetitive, but alpha-ketoisovalerate increased the Vm and Km for adenosine 5'-triphosphate in the presence of inhibitor. In the presence of thiamin pyrophosphate, PDH kinase remained stimulated after chromatography on Sephadex G-25 to remove alpha-ketoisovalerate. The results indicate that acylation of pyruvate dehydrogenase complex by alpha-ketoisovalerate results in PDH kinase stimulation but only in the presence of monovalent cations and thiamin pyrophosphate.
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PMID:Bovine heart pyruvate dehydrogenase kinase stimulation by alpha-ketoisovalerate. 221 97

The effects of various metabolites on pyruvate dehydrogenase (PDH) kinase-catalyzed inactivation of the pyruvate dehydrogenase complex (PDC) were studied in extracts of mitochondria purified from green leaf tissue of Pisum sativum L. Pyruvate was an uncompetitive inhibitor of PDH kinase with respect to ATP whereas ADP was a competitive inhibitor. In the absence of pyruvate a fivefold excess of ADP over ATP was required to inhibit PDH kinase, however, in the presence of pyruvate much lower ADP concentrations were required. Inhibition of PDH kinase by pyruvate and ADP was synergistic and the addition of ADP changed pyruvate from an uncompetitive inhibitor to a noncompetitive inhibitor. This result indicates that pyruvate acts as a "dead-end" inhibitor, binding to the PDH kinase-ADP reaction intermediate. Evidence is also presented that inhibition by pyruvate in the presence of thiamine pyrophosphate is due to the formation of hydroxyethyl thiamine pyrophosphate. The results are discussed in terms of the regulation of PDC activity by pyruvate and ADP during periods of increased demand for carbon skeleton biosynthesis by way of the tricarboxylic acid (TCA) cycle despite constraints imposed on TCA cycle flux by a high ATP/ADP ratio.
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PMID:Mechanism of pyruvate inhibition of plant pyruvate dehydrogenase kinase and synergism with ADP. 232 60

The activities of pyruvate dehydrogenase (PDH) kinase and of PDH kinase activator protein (KAP) were increased 2-2.4-fold during 25 h of culture of hepatocytes from fed rats with glucagon plus n-octanoate. PDH kinase activity in hepatocytes from starved rats (initially 2.2 x fed control) fell during 25 h of culture in medium 199 (to 1.5 x fed control), but was maintained by glucagon plus octanoate. Dibutyryl or 8-bromo cyclic AMP increased PDH kinase activity 2-2.2-fold in hepatocytes from fed rats, but phenylephrine and isoproterenol (isoprenaline) were without effect. Insulin blocked the action of glucagon to increase PDH kinase activity and decreased the effect of octanoate and octanoate plus glucagon. It is suggested that the effects of starvation to increase activities of PDH kinase and of KAP in liver are mediated by alterations in circulating concentrations of glucagon, fatty acids and insulin and in hepatic cyclic AMP.
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PMID:Longer-term regulation of pyruvate dehydrogenase kinase in cultured rat hepatocytes. 253 88


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