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 cerebral ischemia on the activity of pyruvate dehydrogenase (PDH) enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex following 15 min of bilateral common carotid occlusion ischemia and following 15 min, 60 min, and 6 h of recirculation after 15 min of ischemia. In frozen cortical tissue from the same animals, the levels of labile phosphate compounds, glucose, glycogen, lactate, and pyruvate was determined. In cortex from control animals, the rate of [1(-14)C]pyruvate decarboxylation was 9.6 +/- 0.5 nmol CO2/(min-mg protein) or 40% of the total PDHC activity. This fraction increased to 89% at the end of 15 min of ischemia. At 15 min of recirculation following 15 min of ischemia, the PDHC activity decreased to 50% of control levels and was depressed for up to 6 h post ischemia. This decrease in activity was not due to a decrease in total PDHC activity. Apart from a reduction in ATP levels, the acute changes in the levels of energy metabolites were essentially normalized at 6 h of recovery. Dichloroacetate (DCA), an inhibitor of PDH kinase, given to rats at 250 mg/kg i.p. four times over 2 h, significantly decreased blood glucose levels from 7.4 +/- 0.6 to 5.1 +/- 0.3 mmol/L and fully activated PDHC. In animals in which the plasma glucose level was maintained at control levels of 8.3 +/- 0.5 mumol/g by intravenous infusion of glucose, the active portion of PDHC increased to 95 +/- 4%. In contrast, the depressed PDHC activity at 15 min following ischemia was not affected by the DCA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pyruvate dehydrogenase activity in the rat cerebral cortex following cerebral ischemia. 271 7

The effects of monovalent ions on endogenous pyruvate dehydrogenase (PDH) kinase activity in purified bovine heart pyruvate dehydrogenase complex were investigated. Activity of PDH kinase was stimulated 1.9-, 1.95-, 1.65-, and 1.4-fold by 10 mM K+, Rb+, NH+4, and Cs+, respectively, whereas Na+ and Li+ had no effect on PDH kinase activity. The crystal radii of stimulatory ions were in the range of 1.33 to 1.69 A while the crystal radii of nonstimulatory ions were in the range of 0.6 to 0.94 A. Stimulation of PDH kinase by monovalent ions was not pH dependent. Protein dilution studies showed that monovalent ion stimulation was measurable within 10 s after protein addition to PDH kinase assays. Furthermore, stimulation occurred at all protein concentrations tested. At ATP concentrations from 12.5 to 25 microM, K+ and NH+4 stimulation was constant from 0 to 110 and 0 to 30 mM, respectively. At higher ATP concentrations, from 50 to 500 microM, K+ and NH+4 stimulation peaked at approximately 30 and 3 mM, respectively, and thereafter declined as the ion concentration increased. Maximal PDH kinase stimulation by K+ or NH+4 also declined as Na+ was increased from 0 to 120 mM, but at a fixed salt concentration of 120 mM, both K+ and NH+4 stimulated PDH kinase activity. Phosphopeptide analysis demonstrated that K+ and NH+4 stimulated phosphorylation at sites 1 and 2, but that site 3 phosphorylation was relatively constant under all conditions. Thiamin pyrophosphate and 5,5'-dithiobis-(2-nitrobenzoate) blocked monovalent ion stimulation half-maximally at 4 and 6 microM, respectively. However, neither thiamin pyrophosphate nor 5,5'-dithiobis-(2-nitrobenzoate) significantly inhibited PDH kinase activity in the absence of monovalent ions. The results indicate that heart PDH kinase stimulation by monovalent ions does not occur by changing the binding equilibrium between PDH and dihydrolipoyl transacetylase core. Instead, monovalent ions bind and exert their regulatory effects at or near the active site of PDH kinase.
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PMID:Bovine heart pyruvate dehydrogenase kinase stimulation by monovalent ions. 274 10

The putative mediator of intracellular insulin action has been assayed quantitatively by its ability to increase the activity of solubilized pyruvate dehydrogenase (PDH) phosphatase. Conversion of soluble beef heart PDH b to PDH a by PDH phosphatase increased when incubation was carried out in the presence of a crude insulin mediator fraction generated from insulin-treated adipose tissue or liver plasma membranes. Increased PDH phosphatase activity was proportional to the concentration of added insulin mediator. Mediator generation was rapid, with a half-time of approximately 45 sec and was insulin dose dependent. Half-maximal mediator activity was produced at 0.3 nM added insulin, with maximal activity being generated at approximately 3 nM insulin. Mediator activity was significantly decreased at 7 nM insulin, but was increased 4-fold after ethanol extraction. Mediator behaved as an activator of PDH phosphatase, apparently by abolishing the inhibitory effects of ATP on phosphatase activity, but had no effect on PDH kinase activity. The assay of insulin mediator activity described here can be carried out under standardized conditions, in contrast to previously described methods using particulate mitochondrial preparations.
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PMID:Assay of insulin mediator activity with soluble pyruvate dehydrogenase phosphatase. 298 64

The proportion of pyruvate dehydrogenase (PDH) complex in the active dephosphorylated form was decreased (compared with fed lean control mice) in heart muscle mitochondria after the induction of obesity with gold-thioglucose (by 54%) or starvation of lean mice for 48 h (by 81%). The effects of obesity to inactivate PDH complex were demonstrable 4 weeks after administration of gold-thioglucose, and occurred despite significant hyperinsulinaemia in obese animals. Phosphorylation and inactivation of PDH complex in mouse heart muscle in starvation was attributed to a stable increase (2.7-fold) in the activity of PDH kinase as measured in extracts of mitochondria mediated by increased specific activity of a protein activator of PDH kinase (KAP) [Denyer, Kerbey & Randle (1986) Biochem. J. 239, 347-354]. In obese mice no such increase in kinase activity was observed, and we conclude that phosphorylation and inactivation of PDH complex in heart muscle in obesity is not mediated by KAP, but rather is a consequence of increased lipid oxidation.
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PMID:Inactivation of pyruvate dehydrogenase complex in heart muscle mitochondria of gold-thioglucose-induced obese mice is not due to a stable increase in activity of pyruvate dehydrogenase kinase. 313 85

The work investigated the mechanisms for modulation of renal and hepatic pyruvate dehydrogenase complex (PDH) activities after carbohydrate re-feeding of 48 h-starved rats, and identified a regulatory role for tri-iodothyronine. Glucose re-feeding decreased blood concentrations of lipid fuels in both euthyroid and hyperthyroid rats. This treatment was not associated with re-activation of hepatic PDH in either group of rats, or of renal PDH in hyperthyroid rats (where activity was already high), but it increased renal PDH in euthyroid rats. Dichloroacetate (DCA), an activator of PDH kinase, increased renal PDH activities in euthyroid rats, but not hyperthyroid rats, and effects of glucose re-feeding or hyperthyroidism were no longer apparent. These treatments therefore exert their effects on renal PDH through changes in PDH kinase. DCA re-activation of hepatic PDH was more marked in hyperthyroid than in euthyroid rats, suggesting that, under conditions of inhibited kinase activity, PDH phosphatase is more active in livers of hyperthyroid rats. The limited effect of DCA on hepatic PDH in euthyroid rats was potentiated by glucose re-feeding or insulin, but not by inhibition of lipolysis, demonstrating a direct effect of insulin to increase hepatic PDH phosphatase. Glucose re-feeding, inhibition of lipolysis or insulin administration did not increase hepatic PDH in DCA-treated hyperthyroid rats, indicating that effects of hyperthyroidism and of insulin on PDH phosphatase are not additive.
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PMID:Regulation of renal and hepatic pyruvate dehydrogenase complex on carbohydrate re-feeding after starvation. Possible mechanisms and a regulatory role for thyroid hormone. 329 32

In tissue culture of hepatocytes, insulin (0.1-1 munits/ml for 4 h) reversed completely the effects of starvation of rats to decrease the activity of pyruvate dehydrogenase (PDH) complex and to increase the activities of PDH kinase and PDH kinase activator protein. It had no effect in hepatocytes from fed rats. Significant effects of insulin were detected with 0.01 munit/ml after 4 h, and in 1-2 h with 1 munit/ml.
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PMID:Insulin reverses effects of starvation on the activity of pyruvate dehydrogenase kinase in cultured hepatocytes. 331 65

A live dengue-2 (DEN-2) candidate vaccine (strain 16681-PDK 53), attenuated by passage in primary dog kidney cells, was tested in ten adult volunteers for evaluation of the safety, infectivity and immunogenicity of a dose of 1.9-2.7 x 10(4) plaque-forming units. Five of the volunteers were nonimmune to either dengue or Japanese encephalitis (JE) viruses; the other five were nonimmune to dengue but immune to JE. After receiving 1.0 ml of the vaccine subcutaneously, all ten volunteers developed neutralizing antibodies to DEN-2 which were maintained for at least one and a half years. None of the subjects developed abnormal signs or symptoms and the results of clinical chemistry investigations were within normal range throughout the 21 days of observation after the immunization. Virus isolated from one viraemic volunteer retained the small-plaque and temperature-sensitive growth characteristics of the vaccine virus in vitro. Further testing of this candidate vaccine in humans is indicated.
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PMID:Immunization with a live attenuated dengue-2-virus candidate vaccine (16681-PDK 53): clinical, immunological and biological responses in adult volunteers. 349 85

Regulation of the pyruvate dehydrogenase (PDH) complex has been demonstrated to be a key mechanism in the control of carbohydrate oxidation and conservation of glucose carbon. The effect of sterile inflammation and chronic sepsis (small and large abscess) on the activity of the PDH complex was examined in liver and skeletal muscle. Sepsis altered the proportion of PDH in the active, dephosphorylated form. In hepatic tissue, sterile inflammation leads to a 2.5-fold increase in the proportion of active PDH complex compared to fed control. The same increase in the proportion of active PDH complex was observed in rats with a small septic abscess. However, when the severity of septic episode was increased, the proportion of active PDH complex decreased relative to sterile inflammation or small septic abscess animals. A different pattern in the response to sterile inflammation and sepsis on the proportion of active PDH complex was observed in skeletal muscle compared to liver. In contrast to liver, sterile inflammation did not alter the proportion of active PDH in skeletal muscle. In addition, sepsis (either small or large septic abscess) resulted in a 3-fold decrease in the proportion of active PDH relative to fed control or sterile inflammatory animals. The decrease in the proportion of active PDH complex in sepsis was associated with a corresponding increase in the skeletal muscle acetyl-CoA/CoA ratio. The mechanism responsible for lowered PDH complex activity may have been due to increased PDH kinase activity, secondary to increased skeletal muscle acetyl-CoA/CoA ratios.
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PMID:Regulation of glucose metabolism by altered pyruvate dehydrogenase activity. I. Potential site of insulin resistance in sepsis. 352 46

In contrast to the pyruvate dehydrogenase complex (PDC) from animal mitochondria, our in situ and in vitro studies indicate that the ATP:ADP ratio has little or no effect in regulating the mitochondrial pyruvate dehydrogenase complex from green pea seedlings. Pyruvate was a competitive inhibitor of ATP-dependent inactivation (Ki = 59 microM), while the PDC had a Km for pyruvate of microM. Thiamine pyrophosphate, the coenzyme for the pyruvate dehydrogenase (PDH) component of the complex, did not inhibit ATP-dependent inactivation when used alone but it enhanced inhibition by pyruvate. As such, thiamine pyrophosphate was a competitive inhibitor (Ki = 130 nM) of ATP-dependent inactivation. A model is proposed for the pyruvate plus thiamine pyrophosphate inhibition of ATP-dependent inactivation of the pyruvate dehydrogenase complex in which pyruvate exerts its inhibition of inactivation by altering or protecting the protein substrate from phosphorylation and not by directly inhibiting PDH kinase.
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PMID:Regulation of pea mitochondrial pyruvate dehydrogenase complex activity: inhibition of ATP-dependent inactivation. 367 88

Dichloroacetate (DCA) is known to prevent the phosphorylation of the pyruvate dehydrogenase complex (PDHC) by blocking the action of PDH kinase. This action allows the active PDHC to exert its effect on the metabolism of glucose, lactate and alanine to acetyl CoA. DCA has been shown to reduce serum lactate levels in humans and animals in such conditions as diabetes, phenformin-induced hepatic failure, exercise, and endotoxin-induced shock. Lactic acidosis in the brain has often been postulated as a cause of neuronal damage following ischemia and hypoxia. Therefore, we examined the effect of intravenously administered DCA (100 mg/kg) in rats that were rendered hyperglycemic by intravenous glucose (2 g/kg), and then made to undergo 15 minutes of incomplete cerebral ischemia by bilateral carotid ligation and systemic hypotension (mean arterial pressure of 50 mm Hg). DCA significantly reduced serum lactate levels pre-ischemia, but had no effect on serum lactate levels after ischemia induction. Brain levels of lactate, ATP and PCr after 15 minutes of incomplete ischemia were unaffected by DCA. We conclude that in this in-vivo model the control of PDHC activity in the brain may be different than that in the periphery, and that DCA was not effective in reducing brain tissue lactate levels.
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PMID:The effect of dichloroacetate on brain lactate levels following incomplete ischemia in the hyperglycemic rat. 371 55


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