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 mitochondrial kinases responsible for the phosphorylation and inactivation of rat heart pyruvate dehydrogenase complex and the rat liver and heart branched-chain alpha-ketoacid dehydrogenase complexes have been purified to homogeneity. The branched-chain alpha-ketoacid dehydrogenase kinase is composed of one subunit with a molecular weight of 44 kDa; pyruvate dehydrogenase kinase has two subunits with molecular weights of 48 (alpha) and 45 kDa (beta). Proteolysis maps of branched-chain alpha-ketoacid dehydrogenase kinase and the two subunits of pyruvate dehydrogenase kinase are different, suggesting that all subunits are different entities. The alpha subunit of the rat heart pyruvate dehydrogenase kinase was selectively cleaved by chymotrypsin with concomitant loss of kinase activity, as previously shown for the bovine kidney enzyme, suggesting that the catalytic activity of pyruvate dehydrogenase kinase resides in this subunit. Polyclonal antibodies against branched-chain alpha-ketoacid dehydrogenase kinase, purified by an epitope selection method, bound only to the 44 kDa polypeptide of the branched-chain alpha-ketoacid dehydrogenase complex, substantiating that the 44 kDa protein corresponds to the kinase for this complex. Both kinases exhibited strong substrate specificity toward their respective complexes and would not inactivate heterologous complexes. The kinases possessed slightly different substrate specificities toward histones. Phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex by its purified kinase was inhibited by alpha-chloroisocaproate and dichloroacetate, established inhibitors of the phosphorylation of the complex. cDNAs encoding the branched-chain alpha-ketoacid dehydrogenase kinase have been isolated from rat heart and rat liver lambda gt11 libraries. This represents the first successful cloning of a mitochondrial protein kinase. Preliminary data suggest that two different isoforms of the kinase may exist in different ratios in various tissues. No evidence was found for induction of the branched-chain alpha-ketoacid dehydrogenase complex nor its kinase by clofibric acid. Rather, clofibric acid is a potent inhibitor of the activity of the branched-chain alpha-ketoacid dehydrogenase kinase and this may be the molecular mechanism responsible for the myotonic effects of clofibric acid in man.
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PMID:Purification, characterization, regulation and molecular cloning of mitochondrial protein kinases. 149 22

1. The effects of purified diets containing 70% glucose or 70% fructose on the activation state of hepatic pyruvate dehydrogenase (PDHa), activity of mitochondrial PDH kinase, plasma triacylglycerols (TG) and hepatic lipogenesis de novo in rats were measured. 2. Plasma TG were significantly increased in the fructose-fed compared with the glucose-fed group (125 +/- 45 mg/dl versus 57 +/- 19 mg/dl; P less than 0.002) after 3-5 weeks on the diet despite less daily food intake. 3. Hepatic PDHa in fructose-fed rats was 144% of the value in glucose-fed rats (15.4 +/- 1.2% versus 10.7 +/- 0.5%; P less than 0.002), whereas cardiac muscle PDHa was not different (45.5 +/- 6.6% versus 41.0 +/- 7.8%). 4. Intrinsic hepatic PDH kinase activity was decreased to 34% of glucose-fed values by fructose feeding (-k = 3.56 +/- 0.39 versus 10.41 +/- 1.85 min-1; P less than 0.005). 5. The fractional contribution to very-low-density-lipoprotein palmitate from hepatic lipogenesis de novo, measured by a stable-isotope mass-spectrometric method, was 10.49 +/- 2.42% (n = 8) in fructose-fed rats versus 5.55 +/- 1.38% (n = 9) in glucose-fed rats (P less than 0.05), and 2.66 +/- 2.39% (n = 3) in chow-fed rats (P less than 0.05 versus fructose-fed group). The absolute contribution to circulating TG from lipogenesis de novo was also significantly higher in the fructose-fed than in the glucose-fed group (14.9 +/- 5.1 mg/dl versus 2.9 +/- 0.6 mg/dl; P less than 0.05) 6. Portal insulin concentrations were significantly higher in the fructose-fed rats (206 +/- 49 mu-units/ml versus 81 +/- 15 mu-units/ml; P less than 0.05). 7. In conclusion, dietary fructose appears to have a specific activating effect on hepatic PDH, mediated at least in part by inhibition of PDH kinase. These results are consistent with increased flux through hepatic PDH and synthesis of new fat, not just increased re-esterification of non-esterified fatty acids.
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PMID:Mechanisms of fructose-induced hypertriglyceridaemia in the rat. Activation of hepatic pyruvate dehydrogenase through inhibition of pyruvate dehydrogenase kinase. 155 57

Starvation for 48 h elicited a 74% increase in hepatic pyruvate dehydrogenase (PDH) kinase activity, measured directly by 32Pi-incorporation from [gamma-32P]ATP into a synthetic peptide corresponding to the major phosphorylation site on E1. The administration of chow ad libitum to previously-starved rats suppressed hepatic PDH kinase activity by only approx. 20% within 2 h of re-feeding, and the relatively high activity of PDH kinase was associated with continued suppression of PDC complex re-activation. Whereas there was no further decline in PDH kinase activity over the next 2 h, PDC re-activation to the fed value was observed during this time interval. PDH kinase activity decreased to fed values only after 8 h.
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PMID:Hepatic pyruvate dehydrogenase kinase activities during the starved-to-fed transition. 155 50

1. The effects of recombinant human tumour necrosis factor alpha (TNF) and murine interleukin-1 alpha (IL-1) on the activation state of the hepatic pyruvate dehydrogenase complex (PDHa), the activity of mitochondrial PDH kinase, hepatic lipogenesis de novo and plasma triacylglycerol (TG) concentrations were studied. 2. Monokine effects depended upon prior nutritional state. In rats fasted for 20 h or 45 h before monokine administration and refeeding (orally or with intravenous glucose), PDHa, TG and hepatic lipogenesis were not increased. In rats fed ad libitum, treatment with TNF plus IL-1 increased the contribution of hepatic lipogenesis to circulating TG to 550% of control values (P = 0.03) and plasma TG concentrations to 159% (P = 0.02), whereas PDHa increased slightly to 120% (P = 0.02) and liver glycogen content fell to 45.8% (P = 0.05) of control values. 3. Intrinsic hepatic PDH kinase activity was not changed by monokine treatment in rats fed ad libitum. 4. The increased lipogenesis de novo showed no correlation (r2 = 0.05, not significant) with hepatic PDHa in individual animals fed ad libitum. 5. In conclusion, these results suggest that monokines increase pyruvate flux through hepatic PDH in vivo in rats fed ad libitum primarily by mechanisms other than covalent modification of PDH. Prior nutritional status exerts a permissive effect for monokine stimulation of PDHa and lipogenesis, consistent with a substrate-mediated action, but the mechanism of this permissive effect remains uncertain.
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PMID:Effects of recombinant monokines on hepatic pyruvate dehydrogenase, pyruvate dehydrogenase kinase, lipogenesis de novo and plasma triacylglycerols. Abolition by prior fasting. 159 92

Rat liver pyruvate dehydrogenase (PDH) kinase activator protein (KAP), a free PDH kinase readily separable from PDH complex and its intrinsic kinase, has been purified to apparent homogeneity from liver mitochondria of fed and 48-h starved rats. On SDS-PAGE an apparently single band of M(r) 45 kDa was obtained. N-Terminal amino acid sequence analyses (8-10 cycles) confirmed the presence of a single peptide in each case. The specific activity of the purified KAP from 48-h starved rats (14,413 U/mg protein) was 4.5-fold greater than that from fed rats.
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PMID:Purification and partial characterization of rat liver pyruvate dehydrogenase kinase activator protein (free pyruvate dehydrogenase kinase). 164 4

The effects of a series of medium-chain fatty acids (C6-C12) on glucose metabolism in isolated acini from lactating rat mammary glands have been studied. Hexanoate (C6) octanoate (C8) and decanoate (C10), but not laurate (C12), decreased [1-14C]glucose conversion into [14C]lipid and the production of 14CO2 (an index of the pentose phosphate pathway). With hexanoate and octanoate, glucose utilization was decreased, whereas decanoate had a slight stimulatory effect on glucose utilization, but there was a large accumulation of lactate. Addition of dichloroacetate (an inhibitor of pyruvate dehydrogenase kinase) decreased this accumulation of lactate and stimulated the conversion of [1-14C]glucose into [14C]lipid and 14CO2. Insulin had no effect on the rate of glucose utilization in the presence of hexanoate. It stimulated the rate in the presence of octanoate and laurate and increased the conversion of [1-14C]glucose into [14C]lipid in the presence of octanoate, decanoate or laurate. The major fate of 1-14C-labelled medium-chain fatty acids (C6, C8 and C12) was conversion into [14C]lipid. The proportion converted into 14CO2 decreased with increasing chain length, whereas the rate of [14C]lipid formation increased. It is concluded that the interactions between medium-chain fatty acids and glucose metabolism represent a feed-back mechanism to control milk lipid synthesis, and this may be important when milk accumulates in the gland.
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PMID:Chain-length dependency of interactions of medium-chain fatty acids with glucose metabolism in acini isolated from lactating rat mammary glands. A putative feed-back to control milk lipid synthesis from glucose. 173 63

Rat heart branched chain alpha-ketoacid dehydrogenase kinase (BCKDH kinase) and pyruvate dehydrogenase kinase (PDH kinase) were purified from their respective complexes to apparent homogeneity. BCKDH kinase consisted of one subunit with molecular weight 44,000-45,000 Da, whereas PDH kinase consisted of two subunits with molecular weight 48,000 Da (alpha) and 45,000 Da (beta) as previously shown for the bovine kidney enzyme (Stepp et al., 1983, J. Biol. Chem. 258, 9454-9458). Proteolysis maps of BCKDH kinase and the two subunits of PDH kinase were different, suggesting that all subunits are different entities. The alpha subunit of the rat heart PDH kinase could be cleaved selectively by chymotrypsin with concomitant loss of kinase activity, as previously shown for the bovine kidney enzyme, suggesting that the catalytic activity of PDH kinase resides in the alpha subunit. The beta subunit appeared to be a different entity unique to the PDH kinase. Both kinases exhibited marked substrate specificity toward their respective complexes and would not inactivate heterologous complexes. The kinases possessed slightly different substrate specificity toward histones. BCKDH kinase preferentially phosphorylated histones in the order f1 greater than f2B much greater than f2A much greater than f3. The relative order for PDH kinase was the same, but f2A and f3 were considerably better substrates than they were for BCKDH kinase. These observations suggest that the kinases have different requirements for the structure of the protein at their phosphorylation sites.
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PMID:Purification and comparative study of the kinases specific for branched chain alpha-ketoacid dehydrogenase and pyruvate dehydrogenase. 182 99

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 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


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