Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As is the case with many other peptide hormones of the brain and intestine, the formation of biologically active gastrin from a glycine-extended processing intermediate occurs via the action of a peptidylglycyl alpha-amidating monooxygenase (PAM). The observation that gastrin exists primarily as unamidated precursors in the pituitary but as amidated gastrin in the antrum prompted this study to examine whether the amidating enzymes in the two organs were different in their characteristics. Amidating activity was quantified by measuring the conversion of glycine-extended tridecagastrin (G13-Gly) to amidated tridecagastrin and glycine-extended hexapancreatic polypeptide (PP6-Gly) to amidated hexapancreatic polypeptide by radio-immunoassay. Two molecular forms of amidating activity were identified in both the porcine antrum and pituitary. The first, PAM-A, had an apparent Mr of 51,000 and a net negative charge at pH 7.0, whereas PAM-B was smaller (Mr approximately 30,000) and had a net positive charge at pH 7.0. Both molecular forms were similar in their cofactor requirements (copper, ascorbic acid, and catalase) and pH optima in the antrum and pituitary. The Km was significantly lower and the Vmax higher for PP6-Gly than for G13-Gly in the pituitary and antrum. These data suggest that although there is no difference between antral and pituitary PAM, the selective affinity of PAM for certain substrates may provide a mechanism for the differential amidation of different hormones within a given tissue or cell.
 ...
PMID:Gastrin-amidating enzyme in the porcine pituitary and antrum. Characterization of molecular forms and substrate specificity. 198 4

Prolonged achlorhydria leads to hypergastrinemia which must be matched by increased gastrin production. The extent to which the balance between synthesis and storage or secretion is shifted in achlorhydria remains uncertain. In the present study, rats were treated for 14 days with the hydrogen-potassium-stimulated ATPase inhibitor omeprazole, and the effects on plasma and tissue gastrin concentrations and on the abundance of gastrin messenger RNA were examined. To calculate the fractional release rates of gastrin, the metabolic clearance rate of synthetic unsulfated rat heptadeca peptide gastrin in anesthetized rats was also measured. Treatment with omeprazole for 14 days led to a profound hypergastrinemia, a twofold increase in antral gastrin stores, and a tenfold increase in messenger RNA. Calculations based on the metabolic clearance rate for rat heptadecapeptide gastrin suggested that in control rats, about 0.08% of stored gastrin was released per minute compared with about 0.4% in omeprazole-treated rats. No evidence was observed to suggest that changes in the efficiency of conversion of Gly-extended gastrins to amidated peptides were of any significance in accounting for the increased production of amidated gastrin. The increased gastrin synthesis in achlorhydria is therefore attributable to increased messenger RNA levels; most of the increase in gastrin production is directly secreted as changes in the stores of gastrin appear to be of lesser importance.
 ...
PMID:The secretory kinetics of the G cell in omeprazole-treated rats. 201 68

Formation of biologically active amidated gastrin from glycine-extended progastrin processing intermediates (G-Gly) is achieved via the action of peptidyl-glycyl alpha-amidating monooxygenase. Since this enzyme requires copper for optimal activity, we examined the effects of a known copper chelator, diethyldithiocarbamate (DDC), on gastrin posttranslational processing and gastric acid secretion in vivo. DDC (400 mg.kg-1.day-1 ip X 3 days) administered to male Sprague-Dawley rats decreased antral amidated gastrin content, but increased antral G-Gly content. The ratio of amidated gastrin to G-Gly, which reflects in situ amidating activity, was decreased in DDC-treated rats. In contrast, tissue amidating potential, assayed directly under optimal copper concentrations in vitro, was increased in the antrum and unchanged in the pituitary. DDC markedly increased both basal and gastrin-stimulated gastric acid outputs despite the presence of normal serum amidated gastrin levels. These results suggest that copper chelation with DDC inhibits amidating activity in situ but selectively increases antral amidating enzyme synthesis. The marked increase in acid secretion despite normal circulating amidated gastrin concentrations, combined with the enhanced secretory response to exogenously administered gastrin, suggests the possibility that gastrin receptors are upregulated by the events precipitated via DDC administration.
 ...
PMID:Inhibition of the alpha-amidation of gastrin: effects on gastric acid secretion. 215 43

Various gastrin analogues and CCK-8 (Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2) are hydrolyzed in vitro by angiotensin-converting enzyme (ACE), the main and initial cleavage occurring at the Met-Asp (or Leu-Asp) bond, releasing the C-terminal dipeptide amide Asp-Phe-NH2. Tetragastrin analogues (e.g., Boc-Trp-Leu-Asp-Phe-NH2) are degraded by a vesicular membrane fraction from rat gastric mucosa, yielding the C-terminal dipeptide Asp-Phe-NH2. We report here on the degradation of gastrin analogues and CCK-8 by a gastric mucosal cell preparation containing specific gastrin receptors. We have shown that gastrin analogues were specifically degraded by gastric mucosal cells from different species (e.g., rabbit and dog) at 37 degrees C (pH 7.4), releasing the C-terminal dipeptide Asp-Phe-NH2, similarly to ACE. This cleavage was found to be temperature and pH sensitive, and was inhibited by metalloproteinase inhibitors and by captopril, strongly suggesting that this enzymatic system closely resembles ACE. We have also demonstrated that a close correlation seems to exist between the apparent affinity of the gastrin analogues for gastrin receptors on gastric mucosal cells, and their ability of being hydrolyzed by this cell preparation. Moreover, all gastrin analogues which have been demonstrated to act as gastrin antagonists remained unaffected in the incubation conditions.
 ...
PMID:ACE-like hydrolysis of gastrin analogs and CCK-8 by fundic mucosal cells of different species with release of the amidated C-terminal dipeptide. 216 79

Two gastrin analogs containing a D- and a L-tetrafluorinated tyrosyl residue (Arg-Arg-Leu-Glu-Glu-Glu-Glu-Glu-Ala-(F4)Tyr-Gly) were synthesized and tested as substrates and inhibitors of the insulin receptor kinase. No phosphorylation of these peptides was observed, but both gastrin analogs were effective inhibitors in the microM range. Although the D- and L-tetrafluorotyrosine-gastrin analogs differ in the sequence by only 1 amino acid residue, a different inhibitory pattern was obtained with the insulin receptor. The inhibition of all-L-isomer is competitive with respect to both the protein substrate, reduced, S-carboxymethylated, and maleylated lysozyme (RCMM-lysozyme), and ATP with a Ki value of 4 microM. This result corroborates a previous finding (Walker, D. H., Kuppuswamy, D., Visvanathan, A., and Pike, L. J. (1987) Biochemistry 26, 1428-1433) that the kinetic mechanism for insulin receptor is a random Bi Bi mechanism. Different from the L-isomer, the D-analog is competitive to RCMM-lysozyme and noncompetitive toward ATP and gives an apparent inhibition constant of 20 microM. A free tetrafluorotyrosine also shows a competitive inhibition to protein substrate, RCMM-lysozyme (Ki = 18 mM) whereas free tyrosine shows no effect on the activity of insulin receptor. These results show the importance of the charge state and nucleophilicity of the phenolic component in substrate recognition and catalysis and provide a rationale for the design of inhibitors of tyrosyl phosphorylation.
 ...
PMID:A rationale for the design of an inhibitor of tyrosyl kinase. 216 84

To characterize directly the ability of cholecystokinin (CCK) to interact with receptors on the sphincter of Oddi (SO), we measured binding of 125I-labeled Bolton-Hunter-labeled COOH-terminal octapeptide of cholecystokinin (125I-BH-CCK-8) to tissue sections from the guinea pig SO. Autoradiography localized binding of 125I-BH-CCK-8 over the SO smooth muscle layer. Binding was saturable, specific, dependent on time, pH, and temperature, and was reversible. Binding of 125I-BH-CCK-8 was inhibited by various CCK receptor agonists with the following potencies: CCK-8 much greater than des(SO3)CCK-8 much greater than gastrin-17-I and by various CCK receptor antagonists with the following potencies: L-364,718 greater than proglumide analogue 10 much greater than carbobenzoxy-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-NH2 greater than N2,O2' dibutyryl guanosine 3',5'-cyclic monophosphate. The potencies of agonists in stimulating and of antagonists in inhibiting CCK-8-stimulated SO contractions correlated closely with their abilities to inhibit binding of 125I-BH-CCK-8. Analysis of binding of 125I-BH-CCK-8 to SO tissue sections revealed two classes of CCK binding sites: a high-affinity site [dissociation constant (Kd) 0.2 nM] and a low-affinity site (Kd 70 nM). Atropine or tetrodotoxin (TTX) caused a similar rightward shift of the CCK-8 dose-response curve for stimulation of SO contraction. Comparison of receptor occupation to CCK-8-induced contraction suggested that CCK-8 occupation of the high-affinity binding site correlated with contraction in the absence of atropine and the low-affinity CCK binding with contraction in the presence of atropine or TTX.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Characterization of cholecystokinin receptors on the sphincter of Oddi. 224 Feb 27

We previously demonstrated that extremely high amounts of N-terminal big gastrin (G-34) fragments are excreted in human urine and three of them are N-terminal octa-, nona-, and decapeptide of G-34. Our subsequent examination revealed that there exists a considerable amount of another N-terminal G-34 fragment in urine, less hydrophobic than the three peptides. We purified this fragment from urine of an achlorhydric patient and determined the structure: less than Glu-Leu-Gly-Pro-Gln-Gly. The purification was carried out by Sep-Pak C18 cartridges, Sephadex G-25, and reverse phase HPLC. The structure was determined by a combination of amino acid analysis, amino acid sequence analysis, and mass spectral analysis. N-terminal hexapeptide of G-34 is the second richest component of urinary N-terminal G-34 fragments next to N-terminal octapeptide of G-34 in normal subjects.
 ...
PMID:Purification of N-terminal hexapeptide of big gastrin from human urine. 224 19

We have purified an acidic octapeptide from the neural ganglion of the protochordate Ciona intestinalis by a three-step procedure including C18 Sep-Pak fractionation, MonoQ ion-exchange chromatography, and C4 reversed-phase high-performance liquid chromatography. The purification was monitored by an immunoassay specific for the alpha-carboxyamidated COOH terminus common to the mammalian brain-gut hormones, cholecystokinin and gastrin. Automated Edman degradation revealed the sequence Asn-Tyr-Tyr-Gly-Trp-Met-Asp-Phe. In accordance with the high acidity of the peptide, amino acid analysis after cleavage with aminopeptidase M showed that both tyrosyl residues are sulfated. Hence, the structure is Asn-Tyr(SO3)-Tyr(SO3)-Gly-Trp-Met-Asp-Phe-NH2, as also confirmed by identity with the synthetic disulfated peptide in different chromatographic systems. The occurrence of two consecutively sulfated tyrosyl residues after a neutral residue challenges present concepts of consensus sites for tyrosyl sulfation. We conclude that the structure of the peptide, named cionin, suits that of a common ancestor for cholecystokinin and gastrin.
 ...
PMID:Cionin: a disulfotyrosyl hybrid of cholecystokinin and gastrin from the neural ganglion of the protochordate Ciona intestinalis. 230 39

Receptors for the brain and gut peptide cholecystokinin (CCK) have been classified into two classes, CCK-A and CCK-B. To date, peptide analogues with selectivity for the CCK-B receptors have been identified, and selective antagonists for CCK-A and CCK-B receptors have been reported as well; until now, there have been no reports of highly selective CCK-A agonists. Herein we describe the properties of A71378 [desamino-Try(SO3H)-Nle-Gly-Trp-Nle-(N-methyl)Asp-Phe-NH2], a highly selective CCK-A receptor ligand. Characterization of A71378 was carried out in the guinea pig pancreas, cortex, gastric gland, and ileum, as well as in NCI-H345 cells. The IC50 values of A71378 for the pancreatic CCK-A, cortical CCK-B, and gastrin receptor were 0.4 nM, 300 nM, and 1,200 nM, respectively. A71378 proved to be a potent agonist in eliciting pancreatic amylase secretion (EC50 = 0.16 nM) and ileal muscle contraction (EC50 = 3.7 nM). In contrast, A71378 was relatively weak (EC50 = 600 nM) in mobilizing intracellular calcium from NCI-H345 cells, which express CCK-B/gastrin receptors. The high potency and selectivity of A71378 for the CCK-A over CCK-B and gastrin receptors is unprecedented among CCK peptides. Studies on CCK-7 analogues indicate that N-methylation of the Asp residue is responsible for the observed selectivity for CCK-A receptors. This discovery of a selective CCK-A agonist should prove valuable for studies aimed at understanding the physiological roles of CCK-A receptors in the brain and periphery.
 ...
PMID:A71378: a CCK agonist with high potency and selectivity for CCK-A receptors. 233 77

The formation of biologically active gastrin from glycine-extended processing intermediates occurs via the action of a peptide alpha-amidating enzyme. The observation that gastrin exists primarily as unamidated precursors in the pituitary but as amidated gastrin in the antrum prompted these studies to examine whether the amidating enzymes in the two organs were different in their characteristics. Furthermore, the amidating enzyme in the stomach has not previously been characterized in extensive detail. Amidating activity was quantified by measuring the conversion of Tyr-Gly-Trp-Met-Asp-Phe-Gly (glycine-extended hexagastrin) to Tyr-Gly-Trp-Met-Asp-Phe-NH2 (amidated hexagastrin) by radioimmunoassay. The activity of the antral enzyme in both the rat and hog had a similar apparent molecular weight (45,000-60,000), cofactor requirements (copper, ascorbic acid, and catalase), pH optima (5.5-8.5), and Km (12 microM) as the pituitary enzyme. These data suggest that antral and pituitary peptide alpha-amidating enzymes are the same enzyme, thus it is unlikely that differences in amidating enzymes can account for the observed differences in the tissue specific processing of gastrin.
 ...
PMID:Characterization of gastrin amidation in the rat and porcine antrum: comparison with the pituitary. 234 64


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>