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:6.4.1.1 (pyruvate carboxylase)
1,516 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cadmium, in addition to producing a variety of toxic manifestations, is known to accumulate in certain "target" organs which include liver and kidney where histological and functional damage becomes apparent. The daily intraperitoneal injection of cadmium chloride for 21 or 45 days stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-diphosphatase and glucose-6-phosphatase elevated blood glucose and urea, and lowered hepatic glycogen in rats. Whereas chronic Cd treatment failed to alter adenosine-3', 5'-monophosphate phosphodiesterase (PDE) activity, cyclic AMP (cAMY and the activity of basal and fluoride-stimulated forms of hepatic adenylate cyclase (AC) were markedly increased. However, the cAMP binding to hepatic protein kinase was decreased as was the kinase activity ration. An acute dose of Cd decreased hepatic glycogen content and increased blood glucose, serum urea, and hepatic cAMP. Chronic exposure to Cd induced adrenal hypertrophy and augmented adrenal norepinephrine and epinephrine as well as the activity of adrenal tyrosine hydroxylase. This treatment decreased prostatic and testicular weights of mature rats. Although cAMP as well as AC activity of the prostate gland were reduced, cAMP binding to the prostatic protein kinase was increased as was the activity of the cAMP-dependent form of the enzyme. Testicular AC and PDE activities, however, were stimulated, although cAMP remained unaffected. Whereas the activities of the cAMP-dependent and the independent forms of testicular protein kinase were significantly depressed, the binding of cAMP to protein kinase from testes of Cd-treated rats was not affected. In most cases, the observed metabolic alterations persisted up to 28 days on cessation of Cd administration. Subacute Cd treatment suppressed pancreatic function as evidenced by lowered serum immunoreactive insulin (IRI) in presence of hyperglycemia, as well as by partial inhibition of phentolamine-stimulated increases in serum IRI. Although chronic Cd treatment failed to alter the concentration of brain stem norepinephrine and cerebrocortical acetylcholine esterase activity, serotonin levels of brain stem were depressed and the concentration of striatal dopamine and cerebrocortical acetylcholine were significantly elevated when compared with the values seen in control nonexposed animals.
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PMID:Aspects of the biochemical toxicology of cadmium. 17 84

The physiologic significance of glucocorticoids and insulin in the regulation of hepatic gluconeogenesis was investigated during a 48-hr starvation period by studying the factors presumed to control the rate of glucose synthesis in the final gluconeogenetic pathway. Rats were used, in which glucorticoids were removed by adrenalectomy before starvation, and in which serum insulin was kept constant before and after food withdrawal by pre-feeding with a proteinfree diet. It was found that adrenalectomized rats at constantly low serum insulin levels responded to starvation as rapidly, and to the same degree, as intact control subjects (1) by a significant increase in plasma glucagon and, consequently, in hepatic cAMP concentration; (2) by a coordinate elevation of the activities of hepatic pyruvate carboxylase, P-enolpyruvate carboxykinase, and fructose-1,6-diphosphatase; (3) by systematic alterations in the concentration of effectors of gluconeogenetic key enzymes; (4) by a shifting of the cytoplasmic NAD system towards the reduced state; (5) by a decrease in the intrahepatic concentration of glycogenic precursor substrates. These results suggest that the hepatic gluconeogenic response to starvation with respect to the regulatory factors 1-5 occurs independently from changes in the concentration of plasma glucocorticoids and insulin. The crossing over of the gluconeogenetic intermediates between pyruvate and P-enolpyruvate (PEP), which was observed in intact but not in adrenalectomized rats, supports the assumption that during starvation, glucocorticoids enhance the rate of glucose production by the liver predominantly by permitting hepatic cAMP to stimulate the yet undefined mechanism, which has been demonstrated in the isolated perfused rat liver to control the substrate flow between pyruvate and PEP.
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PMID:Physiologic significance of glucocorticoids and insulin in the regulation of hepatic gluconeogenesis during starvation in rats. 18 90

A protein phosphokinase (EC 2.7.1.1.37) was isolated from baker's yeast (Saccharomyces cerevisiae) after a 17,000-fold purification; the purified enzyme is homogeneous according to the criteria of gel electrophoresis and ultracentrifuge analysis. The enzyme has a high isoelectric point of ca. 9 and appears to exist as a monomer with a molecular weight of 42,000 plus or minus 1500. It is neither stimulated by cyclic 3',5'-AMP, -GMP, -CMP or -ump nor inhibited by the regulatory subunit of rabbit muscle protein kinase (Reimann, E. M., Walsh, D. A., and Krebs, E. G. (1971), J. Biol. Chem. 246, 1986). In the presence of divalent metal ions, preferably Mg-2+ or Mn-2+, the enzyme readily transfers the terminal phosphate group of ATP to phosvitin, alphaS1B- and beta a-casein and an NH2-terminal tryptic peptide derived from beta a-casein, but not to protamine, lysine, or arginine-rich histones or to yeast enzymes such as phosphorylase, phosphofructokinase, or pyruvate carboxylase; serine and polyserine were also inactive as phosphate acceptors. Km values of 0.17 mM for beta a-casein and 0.2 mMfor ATP were determined at 10 mM Mg-2+. The urified yeast protein kinase also catalyzes the reverse reaction, namely, the transfer of phosphate from fully phosphorylated beta a-casein or its NH2-terminal peptide to ADP resulting in the formation of ATP. AMP, GDP, UDP, and CDP did not serve as phosphate acceptors in this reaction. As observed by Rabinowitz and Lipmann (Rabinowitz, M., and Lipmann, F. (1960), J. Biol. Chem. 235, 1043) both reactions have different pHoptima with values of 7.5 for the forward reaction (phosphorylation of the proteins) and ca 5.2 for the formation of ATP; both are differently affected by salts. Phosphorylation of beta a-casein with [gamma-32-P]ATP followed by digestion of the labeled protein with trypsin indicated that all the radioactivity was exclusively introduced in an NH2-terminal peptide possessing the unique sequence: Glu-Ser(P)-Leu-Ser(P)-Ser(P)-Ser(P)-Glu-Glu...(Ribadeau-Dumas, B., Brignon, G., Grosclaude, F., and Mercier, J.-C. (1971), eur J. Biochem. 20, 264). By subjecting beta a-casein and its NH2-terminal peptide to the combined action of almond acid phosphatease and purified yeast protein kinase, it was determined that the phosphorylation and dephosphorylation reactions proceed randomly, i.e., all seryl phosphate residues are equally susceptible and that the rate of phosphorylation decreases drastically as the number of bound phosphate groups in the substrate diminishes.
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PMID:Purification and properties of a yeast protein kinase. 23 75

Pi depletion of proximal tubule cells isolated from mouse kidney results in a decrease in the cell content of fructose-2,6-bisphosphate and an increase in the rate of gluconeogenesis from pyruvate, malate and succinate. Gluconeogenesis from glycerol is unaffected by Pi depletion. Introduction of fructose-2,6-bisphosphate into the cytosol of ATP-permeabilized cells is accompanied by a fall in gluconeogenesis. The presence of external Ca2+ stimulates gluconeogenesis. When cytosolic Ca2+ is raised to 1.8 microM by permeabilization, the resealed cells still require 2.5 mM Ca2+ in the bathing medium in order to perform gluconeogenesis at the maximum rate. Cells permeabilized in the presence of cAMP show a decreased rate of glucose production. Phorbol ester stimulates gluconeogenesis provided that the phorbol treatment is performed in the absence of Ca2+ ions. It is suggested that Pi depletion may stimulate pyruvate carboxylase activity and facilitate the entry of certain gluconeogenic substrates into mitochondria. It is also proposed that important aspects of the control of renal gluconeogenesis by parathyroid hormone are mediated by protein kinase C.
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PMID:Studies of the regulation of renal gluconeogenesis in normal and Pi depleted proximal tubule cells. 234 Jun 30

Atrial natriuretic peptide (5-28AA; ANP) and atrial extract (ANS) stimulated rat renal gluconeogenesis in cortical tubule suspension in a dose dependent fashion only from substrates that enter gluconeogenesis via phosphoenol-pyruvate carboxylase. The effects of ANP and ANS were significantly potentiated by cAMP and cGMP, whereas methoxamine showed no effect. Extracellular calcium revealed a key role for ANP and ANS response to gluconeogenesis: a concentration of calcium higher than 1 mM was essential. Isolated cells from cortex which lost cell membrane polarity by warming but responded solely to cAMP and cGMP showed no effect by ANP nor ANS. These data suggest that ANP or ANS may act mainly from the basolateral site in the proximal tubule cell and promote gluconeogenesis through cAMP and/or cGMP system.
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PMID:Atrial natriuretic peptides stimulate renal gluconeogenesis. 299 Apr 70

1. In epididymal adipose tissue synthesizing fatty acids from fructose in vitro, addition of insulin led to a moderate increase in fructose uptake, to a considerable increase in the flow of fructose carbon atoms to fatty acid, to a decrease in the steady-state concentration of lactate and pyruvate in the medium, and to net uptake of lactate and pyruvate from the medium. It is concluded that insulin accelerates a step in the span pyruvate-->fatty acid. 2. Mitochondria prepared from fat-cells exposed to insulin put out more citrate than non-insulin-treated controls under conditions where the oxaloacetate moiety of citrate was formed from pyruvate by pyruvate carboxylase and under conditions where it was formed from malate. This suggested that insulin treatment of fat-cells led to persistent activation of pyruvate dehydrogenase. 3. Insulin treatment of epididymal fat-pads in vitro increased the activity of pyruvate dehydrogenase measured in extracts of the tissue even in the absence of added substrate; the activities of pyruvate carboxylase, citrate synthase, glutamate dehydrogenase, acetyl-CoA carboxylase, NADP-malate dehydrogenase and NAD-malate dehydrogenase were not changed by insulin. 4. The effect of insulin on pyruvate dehydrogenase activity was inhibited by adrenaline, adrenocorticotrophic hormone and dibutyryl cyclic AMP (6-N,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate). The effect of insulin was not reproduced by prostaglandin E(1), which like insulin may lower the tissue concentration of cyclic AMP (adenosine 3':5'-cyclic monophosphate) and inhibit lipolysis. 5. Adipose tissue pyruvate dehydrogenase in extracts of mitochondria is almost totally inactivated by incubation with ATP and can then be reactivated by incubation with 10mm-Mg(2+). In this respect its properties are similar to that of pyruvate dehydrogenase from heart and kidney where evidence has been given that inactivation and activation are catalysed by an ATP-dependent kinase and a Mg(2+)-dependent phosphatase. Evidence is given that insulin may act by increasing the proportion of active (dephosphorylated) pyruvate dehydrogenase. 6. Cyclic AMP could not be shown to influence the activity of pyruvate dehydrogenase in mitochondria under various conditions of incubation. 7. These results are discussed in relation to the control of fatty acid synthesis in adipose tissue and the role of cyclic AMP in mediating the effects of insulin on pyruvate dehydrogenase.
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PMID:Regulation of adipose tissue pyruvate dehydrogenase by insulin and other hormones. 515 98

The role of thyroid hormones in the metabolic adaptation to starvation was investigated in vivo. Glucose production, measured by tracer technique, was enhanced in hyperthyroid (185%) and reduced in hypothyroid (39%) 48-hour starved rats (euthyroid control = 100%). Urinary nitrogen excretion was increased in hyperthyroidism (132%) and decreased in hypothyroidism (70%). Compared with euthyroid controls (=100%) significant alterations for the following regulatory parameters of hepatic gluconeogenesis were observed: 1) tissue cAMP (124%/91%) and protein kinase activation (132%/90%), with a corresponding crossover between pyruvate and P-enolpyruvate (-/+/+/-); 2) pyruvate carboxylase (165%/60%), P-enolpyruvate carboxykinase (140%/82%) and fructose-1.6-bis-P-phosphatase activity (99%/61%), and 3) tissue content of the glucogenic amino acids: alanine (187%/66%) and glutamate (187%/88%), aspartate (179%/68%) and glutamate (137%/75%), as well as of oxaloacetate (254%/66%) and malate (164%/104%). The observed alterations in hepatic oligomycine-sensitive oxygen consumption in hyper- (161%) and hypothyroidism (51%) were related to the measured concentration of the intermediates of the citric acid cycle, the energy state and the mitochondrial redox state. In summary, the different rates of hepatic glucose production in hyper- and hypothyroid starved rats observed in vivo can be ascribed to 1) cAMP content, 2) gluconeogenic key enzyme activities, 3) glucogenic precursor supply and 4) cofactor (ATP) availability.
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PMID:Starvation-induced changes of hepatic glucose metabolism in hypo- and hyperthyroid rats in vivo. 626 36

The present study is concerned with the question as to whether the acute treatment of intact rats or hepatocytes with glucagon and dibutyryl cAMP, respectively, leads to a stabilization or an activation of mitochondrial functions, such as state-3 respiration, succinate dehydrogenase activity and pyruvate carboxylase activity. For this purpose, the influence of various parameters of mitochondria preparation (isolation medium, washing steps, storage) as well as of phospholipase A inhibitors (cinchocain, chloroquine) on the expression of the hormone effect was examined. With regard to the above mentioned functions, the values displayed by control mitochondria were found to be considerably higher if mannitol instead of sucrose had been used for isolation. Accordingly, only small effects of hormone treatment became apparent. The addition of cinchocain or chloroquine to the sucrose medium yielded results similar to those obtained with mannitol. Furthermore, the hormone effect on state-3 respiration and succinate dehydrogenase activity was only small if the mitochondria had been prepared faster than usual and had been used without washing. Regarding pyruvate carboxylase, a considerably smaller glucagon effect was observed when it was assayed at 25 degrees C and not (as usual) at 37 degrees C. Our results indicate that glucagon application stabilizes rather than activates mitochondrial functions.
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PMID:Evidence that glucagon stabilizes rather than activates mitochondrial functions in rat liver. 627 81

Pancreatic islets were cultured for 1 day in the presence of 1 to 20 mM glucose and islet proteins were separated on polyacrylamide gels and transferred to nitrocellulose. Pyruvate carboxylase and an unidentified biotin-containing protein were visualized with [125I]streptavidin followed by autoradiography. The amount of pyruvate carboxylase was proportional to the concentration of glucose. Estimates of the amount of the enzyme in islets were made by comparing the density of the islet pyruvate carboxylase band with a standard curve of various amounts of authentic pyruvate carboxylase. This indicated that the enzyme comprised 0.4% of total islet protein. Net synthesis of the enzyme was increased by cAMP and methyl succinate. A nuclear run-on assay showed that glucose caused increases in pyruvate carboxylase and pyruvate dehydrogenase E1 alpha subunit transcripts and decreases in branched chain ketoacid dehydrogenase E1 alpha transcripts in rat insulinoma (RINm5F) cells. Pancreatic islets cultured in the presence of 1 mM glucose for 1 day cannot respond to glucose with insulin release. Previous studies demonstrated that carbon flux into the citric acid cycle intermediates via both carboxylation and decarboxylation is decreased in glucose-incapacitated islets (M. J. MacDonald, 1993, Arch. Biochem. Biophys. 300, 205-214), 1993). The current results support the idea that carboxylation of glucose-derived pyruvate, as well as decarboxylation of pyruvate, is important for glucose-induced insulin secretion.
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PMID:Influence of glucose on pyruvate carboxylase expression in pancreatic islets. 777 76

Mutations in the transcription factor IPF1/PDX1 have been associated with type 2 diabetes. To elucidate beta-cell dysfunction, PDX1 was suppressed by transduction of rat islets with an adenoviral construct encoding a dominant negative form of PDX1. After 2 days, there was a marked inhibition of insulin secretion in response to glucose, leucine, and arginine. Increasing cAMP levels with forskolin and isobutylmethylxanthine restored glucose-stimulated insulin secretion, indicating normal capacity for exocytosis. To identify molecular targets implicated in the altered metabolism secretion coupling, DNA microarray analysis was performed on PDX1-deficient and control islets. Of the 2640 detected transcripts, 70 were up-regulated and 56 were down-regulated. Transcripts were subdivided into 12 clusters; the most prevalent were associated with metabolism. Quantitative reverse transcriptase-PCR confirmed increases in succinate dehydrogenase and ATP synthase mRNAs as well as pyruvate carboxylase and the transcript for the malate shuttle. In parallel there was a 50% reduction in mRNA levels for the mitochondrially encoded nd1 gene, a subunit of the NADH dehydrogenase comprising complex I of the mitochondrial respiratory chain. As a consequence, total cellular ATP concentration was drastically decreased by 75%, and glucose failed to augment cytosolic ATP, explaining the blunted glucose-stimulated insulin secretion. Rotenone, an inhibitor of complex I, mimicked this effect. Surprisingly, TFAM, a nuclear-encoded transcription factor important for sustaining expression of mitochondrial genes, was down-regulated in islets expressing DN79PDX1. In conclusion, loss of PDX1 function alters expression of mitochondrially encoded genes through regulation of TFAM leading to impaired insulin secretion.
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PMID:Oligonucleotide microarray analysis reveals PDX1 as an essential regulator of mitochondrial metabolism in rat islets. 1515 93


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