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)

Muscle glucose uptake is greatly stimulated by moderate exercise, but full oxidation of the glucose to CO2 depends on the activity of the pyruvate dehydrogenase (PDH) complex. Our aim was to determine how PDH complex in different muscle groups responds to varying periods of moderate exercise. Rats were run on a motor-driven treadmill for 5-30 min and muscle PDH complex activity was determined in heart, diaphragm and red quadriceps muscles after isolation of mitochondria in the presence of inhibitors of PDH complex interconversion. In heart and diaphragm muscle, exercise caused an increase in PDH complex activity after 5 min, but this was followed by a significant decrease in activity as exercise progressed. In red quadriceps muscle, PDH complex activity was reduced after 5 min of exercise and was decreased further as exercise continued. We conclude that increased duration of exercise can lead to reduced PDH complex activity in rat muscles. We propose that this is a consequence of elevated fatty acid oxidation, the products of which stimulate PDH kinase. This implies that increased glycolysis to lactate and increased fatty acid oxidation can simultaneously provide energy for contracting muscle.
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PMID:Heterogeneity of response to exercise of rat muscle pyruvate dehydrogenase complex. 196 81

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 presentation and treatment of a central hypoventilation syndrome in a boy with pyruvate dehydrogenase complex (PDHC) deficiency are reported. Dephosphorylated PDHC was assayed in disrupted fibroblasts after pretreatment with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor. Maximal specific activity of activated patient PDHC was 10% to 30% of control values. Patient PDHC activity was not increased by alterations in concentrations of pyruvate or cofactors (thiamine pyrophosphate [TPP], coenzyme A [CoA], oxidized form of nicotinamide adenine dinucleotide [NAD+]). Clinically, normalization of plasma lactate by a high-lipid diet did not prevent slowly progressive neurologic decline. The patient manifested intermittent ataxia, episodic profound weakness, moderate psychomotor retardation, ophthalmoplegia, and retinal pigment epithelial changes. A true central hypoventilation syndrome was documented on the basis of rigorous radiologic, electrophysiologic, and pulmonary function criteria. Theophylline, progesterone, and ritalin neither altered ventilatory response to CO2 nor permitted weaning from the ventilator. In contrast, peripheral chemoreceptor stimulants (intravenous doxapram; oral almitrine) effected an acute doubling of minute ventilation with appropriate decreases in PaCO2. However, a positive response to long-term therapy with almitrine could not be unequivocally shown. It was concluded that measurement of disrupted fibroblast PDHC following dichloroacetate activation constitutes an accurate assay for PDHC deficiency. PDHC deficiency must be considered in the differential diagnosis of the central hypoventilation syndrome; this appears to be the first report of such an association. Finally, a therapeutic trial of a peripheral chemoreceptor agonist is warranted in the management of central hypoventilation syndrome.
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PMID:Central hypoventilation syndrome in pyruvate dehydrogenase complex deficiency. 643 1

Previous studies have demonstrated that pyruvate dehydrogenase kinase (PDHK) activity in extracts of rat cardiac mitochondria is increased @two-fold by providing a high-fat diet for 28 days. The present study sought to establish the factor(s) that might underlie the response of cardiac PDHK to the provision of a high-fat diet. ELISA assays of PDHKII, conducted over a range of PDHK activities, demonstrated that the increase in cardiac PDHK activity was not due to an increase in mitochondrial immunoreactive PDHKII concentration. The pyruvate concentration giving 50% active PDHC (PDHa) in mitochondria incubated with respiratory substrates was unaffected by high-fat feeding, demonstrating a dissociation between increased PDHK activity and altered sensitivity of PDHK to suppression by pyruvate. In cardiac myocytes cultured (25 h) with n-octanoate (1 mm) plus dibutyryl cAMP (50 microM), insulin at 12.5 microU/ml, 25 microU/ml and 75 microU/ml, suppressed PDHK activities in cells prepared from control rats, but insulin at concentrations <100 microU/ml failed to suppress PDHK activities in cardiac myocytes prepared from high-fat-fed rats. In vivo, cardiac insulin sensitivity (assessed by euglycaemic hyperinsulinaemic clamp in combination with 2-[3H] deoxyglucose administration) was suppressed after high-fat feeding. A sustained (24 h) two- to four-fold elevation in plasma insulin concentration (achieved by insulin infusion via osmotic pumps) did not affect PDHK activity in hearts of control rats. In contrast, PDHK activity in hearts of high-fat-fed rats was suppressed to values not significantly different from (insulin-infused) control rats. Basal and agonist-stimulated cAMP concentrations were unaffected by high-fat-feeding or insulin. Furthermore, rates of palmitate oxidation (to CO2) in cardiac myocytes (in the absence or presence of insulin or adrenergic agonists) were not statistically significantly affected by high-fat-feeding. The results indicate that an impaired action of insulin to suppress PDHK participates in the mechanism by which increased PDHK activity is achieved in response to high-fat feeding, but insulin does not act through decreasing cAMP concentrations or suppressing fatty acid oxidation.
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PMID:Molecular mechanisms underlying the long-term impact of dietary fat to increase cardiac pyruvate dehydrogenase kinase: regulation by insulin, cyclic AMP and pyruvate. 923 40