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)

PDC (pyruvate dehydrogenase complex) catalyses the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle. Regulation of PDC determines and reflects substrate preference and is critical to the 'glucose-fatty acid cycle', a concept of reciprocal regulation of lipid and glucose oxidation to maintain glucose homoeostasis developed by Philip Randle. Mammalian PDC activity is inactivated by phosphorylation by the PDKs (pyruvate dehydrogenase kinases). PDK inhibition by pyruvate facilitates PDC activation, favouring glucose oxidation and malonyl-CoA formation: the latter suppresses LCFA (long-chain fatty acid) oxidation. PDK activation by the high mitochondrial acetyl-CoA/CoA and NADH/NAD(+) concentration ratios that reflect high rates of LCFA oxidation causes blockade of glucose oxidation. Complementing glucose homoeostasis in health, fuel allostasis, i.e. adaptation to maintain homoeostasis, is an essential component of the response to chronic changes in glycaemia and lipidaemia in insulin resistance. We develop the concept that the PDKs act as tissue homoeostats and suggest that long-term modulation of expression of individual PDKs, particularly PDK4, is an essential component of allostasis to maintain homoeostasis. We also describe the intracellular signals that govern the expression of the various PDK isoforms, including the roles of the peroxisome proliferator-activated receptors and lipids, as effectors within the context of allostasis.
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PMID:Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. 1464 Oct 14

During exercise in human skeletal muscle, the proportion of carbohydrate derived acetyl-CoA is determined at least in part by the activity of the PDH (pyruvate dehydrogenase) complex. Inhibition of the complex is achieved through reversible phosphorylation of the E1 subunit by a family of PDH kinase isoforms (PDK1-4) while dephosphorylation and activation of the complex is catalysed by a pair of intrinsic PDH phosphatases (PDP1 and 2). In general, the relative activity of the kinases and phosphatases is determined by a host of intramitochondrial effectors which signal energy charge, substrate and product accumulation, muscle contraction and nutritional status. This review focuses on advances in our understanding in human skeletal muscle of the regulatory signals and changes in gene expression which are important during acute exercise and exercise training, as well as in prolonged situations of altered nutritional status.
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PMID:Regulation of PDH activity and isoform expression: diet and exercise. 1464 Oct 42

Fasting forces adaptive changes in whole body and skeletal muscle metabolism that increase fat oxidation and decrease the oxidation of carbohydrate. We tested the hypothesis that 40 h of fasting would decrease pyruvate dehydrogenase (PDH) activity and increase PDH kinase (PDK) isoform mRNA expression in human skeletal muscle. The putative transcriptional activators of PDK isozymes, peroxisome proliferator-activated receptor-alpha (PPAR-alpha) protein, and forkhead homolog in rhabdomyosarcoma (FKHR) mRNA were also measured. Eleven healthy adults fasted after a standard meal (25% fat, 60% carbohydrate, 15% protein) with blood and skeletal muscle samples taken at 3, 15, and 40 h postprandial. Fasting increased plasma free fatty acid, glycerol, and beta-hydroxybutyrate concentrations and decreased glucose and insulin concentrations. PDH activity decreased from 0.88 +/- 0.11 mmol acetyl-CoA. min(-1). kg wet muscle wt(-1) at 3 h to 0.62 +/- 0.10 (P = not significant) and 0.39 +/- 0.06 (P < 0.05) mmol. min(-1). kg wet mass(-1) after 15 and 40 h of fasting. Although all four PDK isoforms were expressed in human skeletal muscle, PDK-2 and -4 mRNA were the most abundant. PDK-1 and -3 mRNA abundance was approximately 1 and 15% of the PDK-2 and -4 levels, respectively. The 40-h fast had no effect on PDK-1, -2, and -3 mRNA expression. PDK-4 mRNA was significantly increased approximately 3-fold after 15 h and approximately 14-fold after 40 h of fasting. Skeletal muscle PPAR-alpha protein and FKHR mRNA abundance were unaffected by the fast. The results suggest that decreased PDH activation after 40 h of fasting may have been a function of the large increase in PDK-4 mRNA expression and possible subsequent increase in PDK protein and activity. The changes in PDK-4 expression and PDH activity did not coincide with increases in the transcriptional activators PPAR-alpha and FKHR.
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PMID:Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting. 1496 24

Whole body glucose disposal and skeletal muscle hexokinase, glycogen synthase (GS), pyruvate dehydrogenase (PDH), and PDH kinase (PDK) activities were measured in aerobically trained men after a standardized control diet (Con; 51% carbohydrate, 29% fat, and 20% protein of total energy intake) and a 56-h eucaloric, high-fat, low-carbohydrate diet (HF/LC; 5% carbohydrate, 73% fat, and 22% protein). An oral glucose tolerance test (OGTT; 1 g/kg) was administered after the Con and HF/LC diets with vastus lateralis muscle biopsies sampled pre-OGTT and 75 min after ingestion of the oral glucose load. The 90-min area under the blood glucose and plasma insulin concentration vs. time curves increased by 2-fold and 1.25-fold, respectively, after the HF/LC diet. The pre-OGTT fraction of GS in its active form and the maximal activity of hexokinase were not affected by the HF/LC diet. However, the HF/LC diet increased PDK activity (0.19 +/- 0.05 vs. 0.08 +/- 0.02 min(-1)) and decreased PDH activation (0.38 +/- 0.08 vs. 0.79 +/- 0.10 mmol acetyl-CoA.kg wet muscle(-1).min(-1)) before the OGTT vs. Con. During the OGTT, GS and PDH activation increased by the same magnitude in both diets, such that PDH activation remained lower during the HF/LC OGTT (0.60 +/- 0.11 vs. 1.04 +/- 0.09 mmol acetyl-CoA.kg(-1).min(-1)). These data demonstrate that the decreased glucose disposal during the OGTT after the 56-h HF/LC diet was in part related to decreased oxidative carbohydrate disposal in skeletal muscle and not to decreased glycogen storage. The rapid increase in PDK activity during the HF/LC diet appeared to account for the reduced potential for oxidative carbohydrate disposal.
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PMID:Enzymatic regulation of glucose disposal in human skeletal muscle after a high-fat, low-carbohydrate diet. 1531 Jul 47

The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the metabolism of glucose to acetyl-CoA. Phosphorylation of pyruvate dehydrogenase by the pyruvate dehydrogenase kinases (PDK) inhibits pyruvate dehydrogenase complex activity. There are four PDK isoforms, and expression of PDK4 and PDK2 genes is elevated in starvation and diabetes, allowing glucose to be conserved while fatty acid oxidation is increased. In these studies we have investigated the transcriptional mechanisms by which the expression of the PDK4 gene is increased. The peroxisome proliferator-activated receptor gamma coactivator (PGC-1alpha) stimulates the expression of genes involved in hepatic gluconeogenesis and mitochondrial fatty acid oxidation. We have found that PGC-1alpha will induce the expression of both the PDK2 and PDK4 genes in primary rat hepatocytes and ventricular myocytes. We cloned the promoter for the rat PDK4 gene. Hepatic nuclear factor 4 (HNF4), which activates many genes in the liver, will induce PDK4 expression. Although HNF4 and PGC-1alpha interact to stimulate several genes encoding gluconeogenic enzymes, the induction of PDK4 does not involve interactions of PGC-1alpha with HNF4. Using the chromatin immunoprecipitation assay, we have demonstrated that HNF4 and PGC-1alpha are associated with the PDK4 gene in vivo. Our data suggest that by inducing PDK genes PGC-1alpha will direct pyruvate away from metabolism into acetyl-CoA and toward the formation of oxaloacetate and into the gluconeogenic pathway.
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PMID:Cloning of the rat pyruvate dehydrogenase kinase 4 gene promoter: activation of pyruvate dehydrogenase kinase 4 by the peroxisome proliferator-activated receptor gamma coactivator. 1596 3

Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1alpha null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.
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PMID:HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. 1651 2

Pyruvate dehydrogenase (PDH) converts pyruvate to acetyl-CoA, links glycolysis to the Krebs cycle, and plays an important role in glucose metabolism and insulin secretion in pancreatic beta cells. In beta cells from obese and Type 2 diabetic animals, PDH activity is significantly reduced. PDH is negatively regulated by multiple pyruvate dehydrogenase kinase (PDK) isotypes (PDK subtypes 1-4). However, we do not know whether fatty acids or high glucose modulate PDKs in islets. To test this we determined PDH and PDK activities and PDK gene and protein expression in C57BL/6 mouse islets. Both high palmitate and high glucose reduced active PDH activity and increased PDK activity. The gene and protein for PDK3 were not expressed in islets. Palmitate up-regulated mRNA expression of PDK1 (2.9-fold), PDK2 (1.9-fold), and PDK4 (3.1-fold). High glucose increased PDK1 (1.8-fold) and PDK2 (2.7-fold) mRNA expression but reduced PDK4 mRNA expression by 40 percent in cultured islets. Changed PDK expression was confirmed by Western blotting. These results demonstrate that in islet cells both fat and glucose regulate PDK gene and protein expression and indicate that hyperglycemia and hyperlipidemia contribute to the decline in diabetic islet PDH activity by increasing mRNA and protein expression of PDK.
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PMID:Regulation of PDK mRNA by high fatty acid and glucose in pancreatic islets. 1663 12

The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the oxidation of glucose to acetyl-CoA. Phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK2 and PDK4) inhibits PDC activity. Expression of the PDK genes is elevated in diabetes, leading to the decreased oxidation of pyruvate to acetyl-CoA. In these studies we have investigated the transcriptional regulation of the PDK4 gene by the estrogen-related receptors (ERRalpha and ERRgamma). The ERRs are orphan nuclear receptors whose physiological roles include the induction of fatty acid oxidation in heart and muscle. Previously, we found that the peroxisome proliferator-activated receptor gamma coactivator (PGC-1alpha) stimulates the expression of PDK4. Here we report that ERRalpha and ERRgamma stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism. In addition, both ERR isoforms recruit PGC-1alpha to the PDK4 promoter. Insulin, which decreases the expression of the PDK4 gene, inhibits the induction of PDK4 by ERRalpha and ERRgamma. The forkhead transcription factor (FoxO1) binds the PDK4 gene and contributes to the induction of PDK4 by ERRs and PGC-1alpha. Insulin suppresses PDK4 expression in part through the dissociation of FoxO1 and PGC-1alpha from the PDK4 promoter. Our data demonstrate a key role for the ERRs in the induction of hepatic PDK4 gene expression.
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PMID:Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression. 1707 27

The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activities of dedicated PD kinase isozymes (PDK1, PDK2, PDK3 and PDK4). Via binding to the inner lipoyl domain (L2) of the dihydrolipoyl acetyltransferase (E2 60mer), PDK rapidly access their E2-bound PD substrate. The E2-enhanced activity of the widely distributed PDK2 is limited by dissociation of ADP from its C-terminal catalytic domain, and this is further slowed by pyruvate binding to the N-terminal regulatory (R) domain. Via the reverse of the PDC reaction, NADH and acetyl-CoA reductively acetylate lipoyl group of L2, which binds to the R domain and stimulates PDK2 activity by speeding up ADP dissociation. Activation of PDC by synthetic PDK inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose in insulin-resistant animals. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate.
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PMID:Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. 1731 Feb 82

Coenzyme A (CoA) is the major acyl group carrier in intermediary metabolism. Hopantenate (HoPan), a competitive inhibitor of the pantothenate kinases, was used to chemically antagonize CoA biosynthesis. HoPan dramatically reduced liver CoA and mice developed severe hypoglycemia. Insulin was reduced, glucagon and corticosterone were elevated, and fasting accelerated hypoglycemia. Metabolic profiling revealed a large increase in acylcarnitines, illustrating the role of carnitine in buffering acyl groups to maintain the nonesterified CoASH level. HoPan triggered significant changes in hepatic gene expression that substantially increased the thioesterases, which liberate CoASH from acyl-CoA, and increased pyruvate dehydrogenase kinase 1, which prevents the conversion of CoASH to acetyl-CoA. These results identify the metabolic rearrangements that maintain the CoASH pool which is critical to mitochondrial functions, including gluconeogenesis, fatty acid oxidation, and the tricarboxylic acid and urea cycles.
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PMID:Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis. 1737 44


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