Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect on free plasma amino acids before and after infusion of 1 mg glucagon was studied at rest after an overnight fast in seven patients with compensated liver cirrhosis and in seven healthy controls. Total aminoacidaemia in cirrhotic patients is significantly higher than in controls. Elevated basal levels in cirrhotics are found particularly in tyrosine, citrulline, tryptophane, threonine, phenylalanine, and methionine whereas ornithine and serine levels are decreased. Save for the redox couple cystine-cysteine which increases, glucagon elicits an decrease in most amino acids that is proportionate to their initial level. Total aminoacidaemia decreases in controls and cirrhotics by 14.6 and 9.1 per cent respectively. Serum ammonia level rises significantly in both groups, urea increases only in controls, uricaemia remains virtually unchanged.
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PMID:The effect of glucagon on free plasma amino acids in cirrhotics and healthy controls. 63 37

The effect of metabolic or hormonal status on CoA biosynthesis was studied by comparing the rates of incorporation of [14C]-panthothenate into CoA in fasted and glucose-fed rats. Rat hearts and livers were freeze-clamped 1.5 hours after intravenous injection of [14C] pantothenate. CoA, pantothenate, and other pathway intermediates were separated by chromatography of tissue extracts on DEAE cellulose paper. Compared to the fasted rats, rats forced-fed glucose 0.5 hours before pantothenate injection 69% lower incorporation of radioactivity into CoA in liver, a 69% lower specific radioactivity of liver CoA, a 63% lower specific radioactivity of liver mitochondrial CoA, and a 44% lower incorporation of radioactivity in CoA in heart. The accumulation of labeled pathway intermediates was negligible. The cysteine content of liver was equal for the two conditions. There was no difference in level of unacylated CoASH for fasted and glucose-fed rats, suggesting that hormonal effects on degree of CoA acylation are not involved in this regulator mechanism. The specific radioactivities and concentrations of pantothenate in heart or liver were also nearly equal for the two conditions, so the regulatory mechanism does not involve hormonal effects on pantothenate uptake into tissues. Thus, the effect of glucose-feeding (and related changes of metabolite and insulin-glucagon levels) on the incorporation o[14C] pantothenate into CoA is exerted at a locus on the biosynthetic and/or degradative pathway between pantothenate and CoA.
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PMID:The effect of metabolic state on incorportion of [14C] pantothenate into CoA in rat liver and heart. 64 1

Tryptophanyl peptide bonds are selectively cleaved by N-chlorosuccinimide (NCS) under acidic conditions. All other peptide bonds are resistant to cleabage by this reagent. Optimal conditions for cleavage are: 2 equiv of NCS, pH 4-5, or 50-80% acetic acid for 30 min at room temperature. Under these conditions methionine residues are oxidized to methionine sulfoxides and cysteine. Other amino acids are not modified. The cleavage reaction was studied with several peptides containing tryptophan residueas successfully applied to several proteins. In alpha-lactalbumin, Kunitz trypsin inhibitor ,and apomyoglobin, selective cleavage of the expected tryptophanyl peptide bonds was obtained in 19-58% yield. The glucagon molecule was fragmented into two peptides in 32% yield.
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PMID:Selective chemical cleavage of tryptophanyl peptide bonds by oxidative chlorination with N-chlorosuccinimide. 99 Feb 66

We reported that glucagon and phenylephrine decrease hepatocyte GSH by inhibiting gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis (Lu, S.C., J. Kuhlenkamp, C. Garcia-Ruiz, and N. Kaplowitz. 1991. J. Clin. Invest. 88:260-269). In contrast, we have found that insulin (In, 1 microgram/ml) and hydrocortisone (HC, 50 nM) increased GSH of cultured hepatocytes up to 50-70% (earliest significant change at 6 h) with either methionine or cystine alone as the sole sulfur amino acid in the medium. The effect of In occurred independent of glucose concentration in the medium. Changes in steady-state cellular cysteine levels, cell volume, GSH efflux, or expression of gamma-glutamyl transpeptidase were excluded as possible mechanisms. Both hormones are known to induce cystine/glutamate transport, but this was excluded as the predominant mechanism since the induction in cystine uptake required a lag period of greater than 6 h, and the increase in cell GSH still occurred when cystine uptake was blocked. Assay of GSH synthesis in extracts of detergent-treated cells revealed that In and HC increased the activity of GCS by 45-65% (earliest significant change at 4 h) but not GSH synthetase. In and HC treatment increased the Vmax of GCS by 31-43% with no change in Km. Both the hormone-mediated increase in cell GSH and GCS activity were blocked with either cycloheximide or actinomycin D. Finally, when studied in vivo, streptozotocin-treated diabetic and adrenalectomized rats exhibited lower hepatic GSH levels and GCS activities than respective controls. Both of these abnormalities were prevented with hormone replacement. Thus, both in vitro and in vivo, In and glucocorticoids are required for normal expression of GCS.
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PMID:Insulin and glucocorticoid dependence of hepatic gamma-glutamylcysteine synthetase and glutathione synthesis in the rat. Studies in cultured hepatocytes and in vivo. 135 65

Our present work characterized the role of hormone-mediated signal transduction pathways in regulating hepatic reduced glutathione (GSH) synthesis. Cholera toxin, dibutyryl cAMP (DBcAMP), and glucagon inhibited GSH synthesis in cultured hepatocytes by 25-43%. Cellular cAMP levels exhibited a lower threshold for stimulation of the GSH efflux than inhibition of its synthesis. The effect of DBcAMP was independent of the type of sulfur amino acid precursor and cellular ATP levels and unassociated with increased GSH mixed disulfide formation or altered GSH/oxidized glutathione ratio. In liver cytosols, addition of DBcAMP and cAMP-dependent protein kinase (A-kinase) inhibited GSH synthesis from substrates (cysteine, ATP, glutamate, and glycine) by approximately 20% which was prevented by the A-kinase inhibitor. However, if only substrates of the second step in GSH synthesis were used (gamma-glutamylcysteine, glycine, and ATP), DBcAMP and A-kinase exerted no inhibitory effect. Phenylephrine, vasopressin, and phorbol ester also inhibited GSH synthesis in cultured cells by approximately 20%, and depleted cell GSH independent of the type of sulfur amino acid precursor. Cellular cysteine level was unchanged despite the significant fall in GSH after glucagon or phenylephrine treatment. Pretreatment with either staurosporine, C-kinase inhibitor, or calmidazolium, a calmodulin inhibitor, partially prevented but, together, completely prevented the inhibitory effect of phenylephrine. The same combination had no effect on the inhibitory effect of glucagon. The effects of hormones were confirmed in both the intact perfused liver and after in vivo administration. Thus, two classes of hormones acting through distinct signal transduction pathways may down-regulate hepatic GSH synthesis by phosphorylation of gamma-glutamylcysteine synthetase.
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PMID:Hormone-mediated down-regulation of hepatic glutathione synthesis in the rat. 164 17

Hepatocytes contain the Gi2 and Gi3 forms of the 'Gi-family' of guanine-nucleotide-binding proteins (G-proteins), but not Gi1. The anti-peptide antisera AS7 and I3B were shown to immunoprecipitate Gi2 and Gi3 selectively, and the antiserum CS1 immunoprecipitated the stimulatory G-protein Gs. Treatment of intact, 32P-labelled hepatocytes with one of glucagon, TH-glucagon ([1-N-alpha-trinitrophenylhistidine, 12-homoarginine]glucagon), Arg-vasopressin, angiotensin-II, the phorbol ester TPA (12-O-tetradecanoylphorbol 13-acetate) and 8-bromo-cyclic AMP elicited a time- and dose-dependent increase in the labelling of the alpha-subunit of immunoprecipitated Gi2 which paralleled the loss of ability of low concentrations of the non-hydrolysable GTP analogue guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG) to inhibit forskolin-stimulated adenylate cyclase activity ('Gi'-function). The immunoprecipitation of phosphorylated Gi-2 alpha-subunit by the antiserum AS7 was blocked in a dose-dependent fashion by the inclusion of the C-terminal decapeptide of transducin, but not that of Gz (a 'Gi-like' G-protein which lacks the C-terminal cysteine group which is ADP-ribosylated by pertussis toxin in other members of the Gi family), in the immunoprecipitation assay. No labelling of the alpha-subunits of either Gi3 or Gs was observed. alpha-Gi2 was labelled in the basal state and this did not change over 15 min in the absence of ligand addition. In contrast to the monophasic dose-effect curves seen with vasopressin, angiotensin and TPA, the dose-effect curve for the glucagon-mediated increase in the labelling of alpha-Gi2 was markedly biphasic where the loss of Gi function paralleled the high-affinity component of the labelling of alpha-Gi2 caused by glucagon. TPA, TH-glucagon, angiotensin-II and vasopressin achieved similar maximal increases in the labelling of alpha-Gi2, which was approximately half that found after treatment of hepatocytes with either high glucagon concentrations (1 microM) or 8-bromocyclic AMP. Analysis of the phosphoamino acid content of immunoprecipitated alpha-Gi2 showed the presence of phosphoserine only. Incubation of hepatocyte membranes with [gamma-32P]ATP and purified protein kinase C, but not protein kinase A, led to the incorporation of label into immunoprecipitated alpha-Gi2. This labelling was abolished if membranes were obtained from cells which had received prior treatment with ligands shown to cause the phosphorylation of alpha-Gi2 in intact cells. We suggest that there are two possible sites for the phosphorylation of alpha-Gi2; one for C-kinase and the other for an unidentified kinase whose action is triggered by A-kinase activation.
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PMID:Hormonal regulation of Gi2 alpha-subunit phosphorylation in intact hepatocytes. 211 93

Cathepsins B and H are representative cysteine proteinases localized to lysosomes of a variety of mammalian cells. Previous studies indicated the presence of these enzymes also in secretory granules of endocrine cells. Therefore, the human endocrine pancreas and human insulinomas were investigated by light microscopical immunohistochemistry on serial semithin plastic sections immunostained sequentially for cathepsins B or H and pancreatic hormones. Out of the four established endocrine cell types, insulin (B-) and glucagon (A-) cells showed immunoreactivities for these cathepsins. Cathepsin B immunoreactivities showed a dot-like appearance in A- and B-cells and in insulinoma cells. Immunoreactivities for cathepsin H additionally were found in cell parts containing secretory granules of B-cells and insulinoma cells. By single and double immunoelectron microscopy the dot-like immunoreactivities for cathepsin B were identified as immunoreactive lysosomes of A- and B-cells and insulinoma cells. In addition, some of the secretory granules of A- and B-cells showed cathepsin B immunoreactivities. Cathepsin H immunoreactivities showed an other pattern: they were found regularly in the secretory granules of A- and B-cells and insulinoma cells, and in lysosomes of A-cells. These findings suggest that cathepsins B and H in lysosomes of A- and/or B-cells are involved in the degradation of lysosomal constituents. In secretory granules of these cells, these cysteine proteinases may participate in the processing of the corresponding hormones from their precursor proteins.
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PMID:Immunocytochemical localization of cathepsins B and H in human pancreatic endocrine cells and insulinoma cells. 255 67

By isolated perfused pancreas of Wistar rats the glucose (11 mmol/l) and arginine (10 mmol/l) stimulated insulin (IRI) and glucagon (IRG) secretion was measured in order to investigate the inhibitory activities of somatostatin-14 (SS 14) and the somatostatin analogue [3,14-L-seleno-cysteine, 8-D-tryptophan]-somatostatin (SeSS). SS-14 or SeSS (152.8 nmol/l) inhibit the glucose stimulated IRI secretion by 75 and 65%, respectively. Only the second phase of the biphasic arginine stimulated insulin secretion pattern by 40%. SeSS has under these conditions no effect, whereas 58 nmol/l SS-14 or SeSS show a suppressing effect on the first (20 and 55%, respectively) and second phase (65 and 85%, respectively) of the insulin secretion. Using 5.8 nmol/l SS-14 or SeSS the arginine stimulated IRG secretion was inhibited only in the second phase of the biphasic glucagon secretion pattern by about 40%. 58 nmol/l SS-14 or SeSS show an inhibiting effect on the first and on the second phase of secretion, in both cases about 50%. It is concluded that in the SS-14 molecule the sulfur of cysteine in position 3 and 14 can be exchanged by selenium without modifying the biological activities measured in the glucose or arginine stimulated IRI and IRG secretion in vitro. The D-Trp8 in the SeSS analogue does not show the typical better inhibitory action of D-Trp8-SS-14 on insulin and glucagon secretion compared with SS-14. Possibly the selenium in the SeSS analogue abolishes this effect.
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PMID:[Action of [3,14-L-selenocysteine, 8-D-tryptophan]-somatostatin on insulin and glucagon secretion of the isolated perfused pancrease of the Wistar rat]. 287 14

This study was performed to assess the relationships between prohormone transport and processing in separate cell types in pancreatic islet tissue. Anglerfish islets were subjected to pulse-chase incubation with [3H]tryptophan and/or [35S]cysteine. Tissue and media were removed at specific time points during the incubation and prepared for electron microscopic examination or biochemical analysis. Specific islet cell types were identified ultrastructurally using protein A gold immunocytochemistry. Transport of newly synthesized peptides through specific subcellular compartments was monitored using electron microscopic autoradiography. Prohormone-product ratios were established by gel filtration and high-performance liquid chromatography analyses of tissue extracts. Complete analyses were performed on A-cells (source of proglucagon-II, glucagon-II, and glucagon-like peptide-II), B-cells (proinsulin and insulin), D-cells (prosomatostatin-II and somatostatin-28), and S-cells (prosomatostatin-I and somatostatin-14). Transport of newly synthesized peptides proceeded from rough endoplasmic reticulum (RER) to Golgi complex and then to mature secretory granules in all cell types. The transport rate was most rapid in A- and B-cells, slower in S-cells, and slowest in D-cells. The T1/2 for conversion of prohormone to product(s) was shortest in S-cells (150 min), slightly longer in B-cells (155 min), much longer in D-cells (259 min), and greater than 300 min in A-cells. These results demonstrate that the transport/prohormone conversion relationships are unique in each of the islet cell types monitored.
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PMID:Simultaneous assessment of prohormone transport and processing in four separate islet cell types: a combined autoradiographic and biochemical study. 290 25

Cathepsin-D has been previously reported to cleave intact PTH into PTH-(1-34) and -(35-84) in membranous fractions of rat and bovine kidney. Whether PTH degradation occurs by intact kidney cells, however, has not been examined in detail. We have, therefore, examined this possibility using an opossum kidney (OK) cell line which possesses the characteristics of proximal renal tubules and responds to PTH. PTH radioimmunoreactivity recovered in trichloroacetic acid-soluble products and in fractions eluted from reverse phase HPLC was measured using an antibody directed to the midregion and C-terminus of PTH. In this study, intact OK cells, but not extracellular enzymes, cleaved human (h) PTH-(1-84) into three discrete fragments which were released into the medium in a time- and temperature-dependent fashion. Half-maximal velocity of PTH-degrading activity (PTHDA) was observed at 9 nM hPTH-(1-84). A 1000-fold molar excess of PTH antagonists [hPTH-(3-34) and [Tyr34]hPTH-(7-34)amide] markedly inhibited PTHDA, whereas ACTH, glucagon, or big gastrin did not suppress it, suggesting an involvement of the PTH receptor in PTHDA. This PTHDA was strongly inhibited by phenylmethylsulfonylfluoride and chymostatin, but not by trypsin inhibitor, elastatinal, or inhibitors of aspartic, cysteine, or metalloproteinases, suggesting that it is due to a seryl chymotrypsin-like endopeptidase. Analysis of chymotrypsin-digested products of hPTH-(1-84) eluted from HPLC exhibited five fragments detected by UV absorbance (210 nm), three of which were measurable by PTH RIA, and each corresponded to the three PTH fragments produced by OK cells. All three fragments were predominantly suppressed in the presence of chymostatin, suggesting that chymotrypsin-like activity is solely responsible for PTHDA in intact OK cells. To further explore the cleavage sites of PTH by chymotrypsin, amino acid analysis of chymotrypsin-cleaved products was performed. The results strongly support the conclusion that a chymotrypsin-like enzyme in OK cells cleaved the hormone between residues 23-24, and 34-35 to produce, at least, hPTH-(24-84) and -(35-84). Lysosomal blockers (chloroquine, ammonium chloride, or monensin) did not affect this PTHDA. Our present study indicates that chymotrypsin-like endopeptidase, but not other endopeptidase or lysosomal enzymes, is responsible for the limited hydrolysis of PTH by intact OK cells.
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PMID:Parathyroid hormone degradation by chymotrypsin-like endopeptidase in the opossum kidney cell. 305 60


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