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 branched-chain alpha-ketoacid dehydrogenase (BCKDH) and pyruvate dehydrogenase (PDH) complexes are regulated by phosphorylation cycles catalyzed by complex-specific protein kinases and phosphoprotein phosphatases. Molecular cloning of these mitochondrial protein kinases has established a new family of protein kinases in eukaryotes that appears related by primary sequence to the histidine protein kinase family of prokaryotes. Changes in the activities of both kinases that are stable, i.e., not caused directly by allosteric effectors, correlate inversely with the changes in the activity states of the complexes that occur in different nutritional states. For example, BCKDH kinase activity is increased and the BCKDH complex activity state is decreased in rats fed diets deficient in protein. The increase in BCKDH kinase activity is due to an increase in the amount of BCKDH kinase protein bound to the BCKDH complex. The message level for BCKDH kinase also increases in the liver of rats starved for protein, suggesting a pretranslational mechanism exists for the long-term regulation of BCKDH kinase. Starvation and high-fat feeding cause a stable increase in PDH kinase activity and a corresponding decrease in activity state of the PDH complex. The mechanism responsible has not been defined.
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PMID:Nutritional regulation of the protein kinases responsible for the phosphorylation of the alpha-ketoacid dehydrogenase complexes. 778 41

Tyrphostins inhibit tyrosine kinases and have little effect on the activity of serine/threonine kinases. Pyruvate dehydrogenase kinase inactivates pyruvate dehydrogenase by phosphorylating serine residues within the multienzyme complex. This serine/theronine kinase represents a new family of protein kinases, and one (tyrphostin 47) of two tyrphostins tested appeared to activate the pyruvate dehydrogenase kinase as determined by [1-14C]-lactate oxidation to 14CO2. Experiments designed to determine if the tyrphostins altered pyruvate dehydrogenase activity in mitochondria prepared from rat epididymal adipocytes using [1-14C]-pyruvate as the substrate demonstrated a dose dependent increase in enzyme activity in the presence of tyrphostin 47, but not in tyrphostin 23. This apparent stimulation of pyruvate dehydrogenase activity was attributed to tyrphostin 47's ability to nonenzymatically decarboxylate [1-14C]-pyruvate, the substrate for the pyruvate dehydrogenase assay. Neither tyrphostin directly altered pyruvate dehydrogenase kinase activity. Therefore, assays utilizing [1-14C]-pyruvate and tyrphostin 47 are subject to analytical interference.
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PMID:Tyrphostin 47 nonenzymatically decarboxylates [1-14C]-pyruvate. 781 37

To identify the molecular determinants for attenuation of wild-type Japanese encephalitis (JE) virus strain SA14, the RNA genome of wild-type strain SA14 and its attenuated vaccine virus SA14-2-8 were reverse transcribed, amplified by PCR and sequenced. Comparison of the nucleotide sequence of SA14-2-8 vaccine virus with virulent parent SA14 virus and with two other attenuated vaccine viruses derived from SA14 virus (SA14-14-2/PHK and SA14-14-2/PDK) revealed only seven amino acids in the virulent parent SA14 had been substituted in all three attenuated vaccines. Four were in the envelope (E) protein (E-138, E-176, E-315 and E-439), one in non-structural protein 2B (NS2B-63), one in NS3 (NS3-105), and one in NS4B (NS4B-106). The substitutions at E-315 and E-439 arose due to correction of the SA14/CDC sequence published previously by Nitayaphan et al. (Virology 177, 541-552, 1990). The mutations in NS2B and NS3 are in functional domains of the trypsin-like serine protease. Attenuation of SA14 virus may therefore, in part, be due to alterations in viral protease activity, which could affect replication of the virus.
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PMID:Molecular basis of attenuation of neurovirulence of wild-type Japanese encephalitis virus strain SA14. 784 60

Glucose is essential for the energy metabolism of some cells and conservation of glucose is obligatory for survival during starvation. The principal site of this glucose conservation is the mitochondrial pyruvate dehydrogenase (PDH) complex, which is regulated by reversible phosphorylation (phosphorylation is inactivating). In cells in which glucose oxidation is switched off during starvation, fatty acids are used as fuel, and acetyl CoA and NADH formed by beta-oxidation promote phosphorylation of PDH complex by activation of PDH kinase. A longer-term mechanism further increases PDH kinase activity in response to cAMP and products of beta-oxidation of fatty acids. Coordinated inhibition of glycolytic flux mediated by effects of citrate on PFK1 and PFK2 in muscles and liver results in an associated inhibition of glucose uptake. Similar mechanisms lead to impaired glucose oxidation in diabetes.
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PMID:Glucose fatty acid interactions and the regulation of glucose disposal. 792 13

Seventy-four in- and out-patients (mean age 71.9 years) with Parkinsonian syndromes (summarized as "PS": idiopathic Parkinson's disease, vascular pseudo Parkinsonian syndrome (VPS), and Parkinson-dementia (PDK)) were prospectively evaluated as to present clinical state according to usual rating scales, as to clinical syndrome and physician's diagnosis and treatment at the start of the illness, and as to current medical and social care. 54% of the patients had history and findings of tremor, 14% had visual hallucinations, 19% had depression. Ratings on part II of the "Unified Parkinson's Disease Rating Scale" (UPDRS) describing "activities of daily living" correlated highly with the ratings of part III ("motor evaluation") and with another activity of daily living scale according to Schwab and England. The mean difference between time of diagnosis and start symptoms (the "diagnostic delay") was nearly 21 months. Initial symptoms did not show an impact on this difference. 68% of patients were presently treated by general physicians and were significantly older than those treated by neurologists. 59% were in-patients during the study and were more likely to carry a diagnosis of VPS or PDK. 75% of those patients who were ever in-patients during their illness had the disease for up to six years before they were first hospitalized. 77% of the patients had drug treatment; 88% of these took L-Dopa preparations. 23% of patients with drug treatment had L-Dopa-associated motor complications. 15% of patients lived alone, 66% with their family, and 19% in a nursing home. 24% of patients had assistance in their household by a professional caretaker. 16% of patients retired early from work. The long-term care of older Parkinsonian patients is a task for general medicine based on neurogeriatric expertise.
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PMID:[Medical management and social status of elderly Parkinson patients]. 797 17

Antibodies were raised in rabbits to free rat liver pyruvate dehydrogenase (PDH) kinase alpha-chain and shown to react with PDH kinase alpha-chain in rat heart and liver PDH complexes, in purified pig heart PDH complex and in bovine kidney dihydrolipoamide acetyltransferase-protein X-PDH kinase subcomplex. E.l.i.s.a for PDHE1 (pyruvate dehydrogenase) and PDH kinase have been developed and applied to assays of these proteins in extracts of rat liver and rat heart mitochondria; the measured immunoreactivities for PDHE1 (heart > liver) and for PDH kinase alpha-chain (liver > heart) paralleled known differences in PDH complex and PDH kinase activities respectively. The results of e.l.i.s.a of PDH kinase alpha-chain in extracts of rat liver mitochondria showed that the effects of starvation to increase PDH kinase activity in vivo, and the effects of dibutyryl cyclic AMP or palmitate to increase PDH kinase activity in hepatocytes cultured in vitro, are due largely (> 90%) to an increase in the specific activity of PDH kinase. The effect, in cultured hepatocytes, of dibutyryl cyclic AMP to increase PDH kinase activity was blocked by cycloheximide; the effect of palmitate was blocked by an inhibitor of carnitine palmitoyltransferase I (Etomoxir), but not by cycloheximide.
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PMID:Role of protein synthesis and of fatty acid metabolism in the longer-term regulation of pyruvate dehydrogenase kinase. 801 Sep 47

In this review, we evaluate the relative regulatory importance of specific strategic enzymes (in particular glycogen synthase, acetyl-CoA carboxylase [ACC] and the pyruvate dehydrogenase complex [PDH]) for carbohydrate utilization as an anabolic precursor and as an energy substrate during the nutritional transitions between the fed and fasted states. The involvement of the specific protein kinases contributing to the inactivation of these enzymes by phosphorylation [cyclic AMP-dependent protein kinase, AMP-activated protein kinase and PDH kinase] in achieving each regulatory response is also assessed. We demonstrate a striking temporal correlation between hepatic glycogen mobilization and PDH and ACC inactivation by phosphorylation during the immediate postabsorptive period; in contrast, rates of hepatic glycogen synthesis and PDH and ACC expressed activities do not change in parallel during refeeding. The results are consistent with shifting of the primary sites of control for overall hepatic carbon flux during the fed-to-starved and starved-to-fed nutritional transitions achieved, at least in part, by a complex pattern of regulation by protein phosphorylation and metabolites which is critically dependent on the precise nutritional status. Data are also presented that demonstrate asynchronous suppression of glucose uptake/phosphorylation and pyruvate oxidation in cardiac and skeletal muscle during progressive starvation. Analogous asynchrony is observed in the reactivation of these processes in cardiac and skeletal muscle during refeeding after starvation. We provide evidence in support of the concept that selective suppression of pyruvate oxidation in oxidative muscles during early starvation and during the initial phase of refeeding is achieved because of differential sensitivity of glucose uptake/phosphorylation and pyruvate oxidation to lipid-fuel utilization. We discuss the relative importance of regulatory events governing local fatty acid production and utilization (via lipoprotein lipase and carnitine palmitoyltransferase 1, respectively) or overall fatty acid supply (dictated by events at the adipocyte) for fuel utilization by muscle during nutritional transitions. Finally, we assess the regulatory importance of glycogen synthesis in determining overall rates of glucose clearance by skeletal muscle during alimentary hyperglycemia and hyperinsulinemia.
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PMID:Mechanisms involved in the coordinate regulation of strategic enzymes of glucose metabolism. 810 32

The pdk gene from Z. mobilis localized on the 4.7-kb SpHI DNA fragment in plasmid pB201 was subcloned using DraI restriction endonuclease into the SmaI site of the phage cloning vector M13mp19. The derivatives of M13mp19 obtained, containing 1.8-kb inserts of the pdk gene in two opposite orientations, were used for DNA sequencing and site-directed mutagenesis. The latter was performed using polymerase chain reaction (PCR) and synthetic deoxyribonucleotides of appropriate structure as primers. In this way a BamHI site near the initial (formylmethionine) codon of the pdk gene was created. After amplification the pdk gene was treated by restriction endonuclease BamHI and cloned into pUC19, and then recloned into shuttle vector pCB20 capable of replicating in both Gram negative and Gram positive bacteria. A recombinant plasmid pCB20pdkI--a derivative of pCB20 carrying the pdk gene under control of the "expression unit" EU19035 containing a bacillar vegetative promoter and an RBS site was obtained. The properties of the pCB20pdkI in E. coli and Bac. subtilis cells were studied. It was shown that pCB20pdkI determines a high level of PDK synthesis in Bac. subtilis. At the same time, it strongly inhibits E. coli cell growth and segregates rapidly from this host.
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PMID:[Design of recombinant plasmids for effective Zymomonas mobilis pyruvate decarboxylase (pdk) gene expression in Bacillus subtilis cells]. 814 44

Nucleotide sequences of the 5' non-coding region and the structural protein genes of the live, attenuated Japanese encephalitis vaccine virus strains SA14-2-8 and SA14-5-3 and the wild-type parental strain SA14/USA were determined. SA14-2-8 differed from SA14/USA by 13 nucleotides and eight amino acids whereas SA14-5-3 differed from SA14/USA by 15 nucleotides and eight amino acids. A comparison of the 5' non-coding region and amino acid sequences of the structural proteins of these two attenuated vaccine strains and of vaccine strains SA14-14-2/PHK and SA14-14-2/PDK with three sequences of their wild-type parent SA14 virus was performed. This revealed only two common amino acid substitutions at positions 138 and 176 in the envelope (E) protein. The substitution at E138 was predicted to cause a change in the secondary structure of the E protein. These two amino acid substitutions in the E protein may contribute to attenuation of the Japanese encephalitis vaccine viruses.
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PMID:Comparison of nucleotide and deduced amino acid sequence of the 5' non-coding region and structural protein genes of the wild-type Japanese encephalitis virus strain SA14 and its attenuated vaccine derivatives. 820 17

The present study investigated the effects of chronic food restriction (achieved by limiting access to food to 2 h daily for up to 8 weeks) on the activity of the active form of pyruvate dehydrogenase (PDHa) in liver. Accelerated and exaggerated activation of hepatic PDH in response to a meal, previously demonstrated to occur within 10 days of food restriction, was demonstrated to persist for 4 and 8 weeks of food restriction, despite a food intake of only 50-60% of controls. Activation of hepatic PDH during feeding in rats subjected to food restriction for 4 weeks was dependent on continued food intake. As a consequence, hepatic PDHa activities in food-restricted rats were suppressed relative to controls for 19 h of the 24 h daily cycle. Curve-fitting by second-order polynomial regression analysis demonstrated a significant positive correlation between hepatic PDHa activity and lipogenic rate over the range of PDHa activities observed during the 2 h feeding period. Increased lipogenesis during feeding in food-restricted rats was not at the expense of hepatic glycogen synthesis or deposition; measurement of concurrent rates of glycogenesis and lipogenesis revealed simultaneous flux through both pathways, but specific activation of lipogenesis. The accelerated re-activation of hepatic PDH observed within 1 h of feeding in rats subjected to 4 weeks of food restriction was facilitated by a failure of the 22 h interprandial fasting period to induce a stable increase in hepatic PDH kinase activity. The present study indicates differential regulation of hepatic PDH kinase activity during periods of food withdrawal between food-restricted rats and starved/re-fed control rats. Such regulation occupies a critical role in determining the rate of activation of hepatic PDH during feeding. In turn, increased activity of hepatic PDHa during feeding in food-restricted rats bears a close positive relationship with hepatic lipogenic rate.
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PMID:The regulation of hepatic carbon flux by pyruvate dehydrogenase and pyruvate dehydrogenase kinase during long-term food restriction. 825 Aug 46


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