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)

Twenty-six peptides, analogs of bombesin (BNa) and gastrin releasing peptide (GRP), have been synthesized by the solid phase method. The synthetic peptides were purified by ion exchange and partition chromatography and shown to be homogenous under various conditions on RP-HPLC. They were further characterized by TLC, amino acid analysis and optical rotation. These peptides have been administered IC to rats and their effects on thermoregulation and glucoregulation have been compared to those of the two natural peptides: frog skin bombesin (BNa) and GRP. Their structure activity relationship is also discussed. The minimum essential residues required for full potency of bombesin-like effects is represented by an acetylated C-terminal 8-peptide fragment, where in position 7 of this peptide an L-amino acid such as alanine, histidine or glutamine, or the D-glutamine residue can be introduced. Modification of the tryptophan [8] and histidine [12] residues by alanine abolished the biological potency of those peptides. Analogs with a free N-terminus were found to express little, but significant, activity, thus indicating that blocked N-terminus is necessary for maximal response. [Ac-Ala7, DAla11]-bombesin (7--14) and [Ac-DGln7 DAla11]-bombesin (7--14) were found to be more potent than bombesin, whereas [Ac-DAla7, DAla11]-bombesin or [Ac-DAla7, DAla11] bombesin N-methylamide were found to have 10 and 1% of bombesin potency, respectively.
 ...
PMID:Bombesin analogs: effects on thermoregulation and glucose metabolism. 734 58

Isolated gastric glands from rabbit were used to characterize the functional cholecystokinin (CCK)-like peptide receptors that mediate pepsinogen secretion. Pepsinogen secretion was stimulated by both CCK octapeptide sulfate (CCK-8) and A-71378, a selective CCK-A-type receptor agonist, with similar mean effective doses (1.0 and 0.8 nM, respectively). Compared with CCK-8, gastrin-17 (G-17-I) showed reduced potency and only partial efficacy for stimulation of pepsinogen secretion while inhibiting the maximal CCK-8-stimulated response. The nonpeptide inhibitors, asperlicin and L-364,718, inhibited pepsinogen secretion with identical pA2 values for antagonism of both CCK and gastrin, indicating that both peptides interact with the same functional receptor. Specific binding of [3H]CCK-8 to isolated chief cell membranes was displaced fully by both CCK and gastrin, indicating full receptor occupancy by both peptides. A novel synthetic peptide analogue, pseudogastrin [(Glu)5-Ala-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2], was used to investigate the structural basis for the lower potency and efficacy of G-17-I. The potency of CCK and gastrin analogues for pepsinogen secretion was found to be dependent on both sulfation of a tyrosine residue and the position of the tyrosine residue relative to the COOH-terminal phenylalanine amide. The efficacy appears to be determined partially by the extended NH2-terminal sequence of G-17-I. The results of the present study are interpreted to show that pepsinogen secretion is mediated by a CCK-A-type receptor and gastrin acts at the same receptor as a partial agonist.
 ...
PMID:Partial agonism by gastrin for a cholecystokinin receptor mediating pepsinogen secretion. 823 15

Val-->Ala mutations within the effective transmembrane segment of a model single-spanning membrane protein, the 50-residue major coat (gene VIII) protein of bacteriophage M13, are shown to have sequence-dependent impacts on stabilization of membrane-embedded helical dimeric structures. Randomized mutagenesis performed on the coat protein hydrophobic segment 21-39 (YIGYAWAMV-VVIVGATIGI) produced a library of viable mutants which included those in which each of the four valine residues was replaced by an alanine residue. Significant variations found among these Val-->Ala mutants in the relative populations and thermal stabilities of monomeric and dimeric helical species observed on SDS/PAGE, and in the range of their alpha-helix-->beta-sheet transition temperatures confirmed that intramembranous valine residues are not simply universal contributors to membrane anchoring. Additional analyses of (i) nonmutatable sites in the mutant protein library, (ii) the properties of the double mutant V29A-V31A obtained by recycling mutant V31A DNA through mutagenesis procedures, and (iii) energy-minimized helical dimer structures of wild-type and mutant V31A transmembrane regions indicated that the transmembrane hydrophobic core helix of the M13 coat protein can be partitioned into alternating pairs of potential protein-interactive residues (V30, V31; G34, A35; G38, I39) and membrane-interactive residues (M28, V29; I32, V33; T36, I37). The overall results consitute an experimental approach to categorizing the distinctive contributions to structure of the residues comprising a protein-protein packing interface vs. those facing lipid and confirm the sequence-dependent capacity of specific residues within the transmembrane domain to modulate protein-protein interactions which underlie regulatory events in membrane proteins.
 ...
PMID:Val-->Ala mutations selectively alter helix-helix packing in the transmembrane segment of phage M13 coat protein. 826 2

As is the case with many other peptide hormones of the brain and gut, gastrin requires a carboxyl-terminal amide moiety for optimal biological activity. In the structure of progastrin, the carboxyl-terminal Phe of gastrin is followed by the sequence Gly93-Arg94-Arg95, which must be processed sequentially by an endoprotease, a carboxypeptidase, and an amidating enzyme to produce amidated bioactive gastrin. To examine the molecular determinants of peptide amidation in vivo, we mutated the wild-type Gly93 residue of progastrin to Ala93 and Ser93 and expressed the three progastrin DNAs in GH3 and MTC 6-23 endocrine cell lines. Although substantial quantities of amidated gastrin were seen in cells expressing wild-type progastrin, replacement of Gly93 with Ala93 completely abolished production of amidated gastrin when the cells were incubated in standard medium containing only L-alanine. In a similar fashion, cells expressing [Ser93]progastrin also demonstrated no production of amidated gastrin. When cells expressing [Ala93]- or [Ser93]progastrin were incubated in the presence of 1 mg/ml D-alanine or D-serine, respectively, a small but consistent amount of amidated gastrin production was detected (< 1% of wild type). These data lead us to conclude that the amidating enzyme has a rigid substrate specificity for a glycine-extended precursor. Furthermore, this in vivo substrate specificity confirms the importance of the pro-S-alpha-hydrogen of the carboxyl-terminal glycine for enzyme-substrate recognition.
 ...
PMID:Substrate specificity of the gastrin-amidating enzyme. 834 Apr 16

Gastrin and its carboxyl-terminal homolog cholecystokinin (CCK) exert a variety of biological actions in the brain and gastrointestinal tract that are mediated in part through one or more G protein-coupled receptors which exhibit similar affinity for both peptides. Genomic clones encoding a human gastrin/CCKB receptor were isolated by screening a human EMBL phage library with a partial-length DNA fragment which was based on the nucleotide sequence of the canine gastrin receptor. The gene contained a 1356-bp open reading frame consisting of five exons interrupted by 4 introns and was assigned to human chromosome 11p15.4. A region of exon 4, which encodes a portion of the putative third intracellular loop, appears to be alternatively spliced to yield two different mRNAs, one containing (452 amino acids; long isoform) and the other lacking (447 amino acids; short isoform) the pentapeptide sequence Gly-Gly-Ala-Gly-Pro. The two receptor isoforms may contribute to functional differences in gastrin- and CCK-mediated signal transduction.
 ...
PMID:The human gastrin/cholecystokinin type B receptor gene: alternative splice donor site in exon 4 generates two variant mRNAs. 841 58

Five tridecapeptides have been identified from the central nervous system of the pond snail, Lymnaea stagnalis. The sequences are Pro-Xaa-Asp-Arg-Ile-Ser-Yaa-Ser-Ala-Phe-Ser-Asp-Phe. NH2, where Xaa is either Tyr or Phe and Yaa either Asn, Ser or Gly. The peptides are named lymnaDFamides to acknowledge identity with the C-terminal dipeptide of the mammalian neuropeptides, cholecystokinin (CCK) and gastrin. They were detected by an antiserum that recognizes the biologically active C-termini of cholecystokinin and gastrin. LymnaDFamide-1 (Xaa = Tyr and Yaa = Asn) had no effect on trout gallbladder, which responds equally to CCK and gastrin. We propose that the lymnaDFamides belong to an Asp-Phe-amide superfamily, which includes CCK and gastrin, and suggest that the widespread CCK/gastrin immunoreactivity in invertebrates is due to peptides belonging to such a superfamily.
 ...
PMID:LymnaDFamides, a new family of neuropeptides from the pond snail, Lymnaea stagnalis. Clue to cholecystokinin immunoreactivity in invertebrates? 847 56

Bombesin (Bn, pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) is one of the most potent peptides, possessing a variety of physiological and pharmacological functions. We find from CD spectroscopy that the eight C-terminal residues of bombesin [Bn(7-14)NH2] have an ordered structure, and replacement of His-12 with Pro of Bn(7-14)NH2 changes the conformation from ordered to a more unordered form. Antibodies to Bn(7-14)NH2 cross-react to Bn and gastrin releasing peptide (GRP) in a dose-dependent manner. Antibodies to the Pro-analog do not recognize Bn or GRP. Substitution of the C-terminal amide by isopropylamide [Bn(7-14)NHC3H7(i)] makes its antibodies more specific to Bn than to GRP. It appears that this region of the peptide is an important antigenic determinant, which makes these antibodies differentiate between BN and GRP.
 ...
PMID:Synthesis and immunological properties of bombesin analogs. 849 14

Elements that confer identity to a tRNA in the cellular environment, where all aminoacyl-tRNA synthetases are competing for substrates, may be delineated by in vivo experiments using suppressor tRNAs. Here we describe the selection of active Escherichia coli tRNAAsp amber mutants and analyze their identity. Starting from a library containing randomly mutated tRNA(CUA)Asp genes, we isolated four amber suppressors presenting either lysine, alanine, or glutamine activity. Two of them, presenting mainly alanine or lysine activity, were further submitted to a second round of mutagenesis selection in order to improve their efficiency of suppression. Eleven suppressors were isolated, each containing two or three mutations. Ten presented identities of the two parental mutants, whereas one had switched from lysine to arginine identity. Analysis of the different mutants revealed (or confirmed for some nucleotides) their role as positive and/or negative determinants in AlaRS, LysRS, and ArgRS recognition. More generally, it appears that tRNAAsp presents identity characteristics closely related to those of tRNALys, as well as a structural basis for acquiring alanine or arginine identity upon moderate mutational changes; these consist of addition or suppression of the corresponding positive or negative determinants, as well as tertiary interactions. Failure to isolate aspartic acid-inserting suppressors is probably due to elimination of the important G34 identity element and its replacement by an antideterminant when changing the anticodon of the tRNAAsp to the CUA triplet.
 ...
PMID:Selection of tRNA(Asp) amber suppressor mutants having alanine, arginine, glutamine, and lysine identity. 880 18

Alanine and N-methylation scans together with molecular modelling were implemented in order to propose a binding conformation of the minimum active fragment of bombesin (BB), Ac-BB[7-14], to the gastrin releasing peptide (GRP) and neuromedin B (NMB) receptors. These data are also used to critically evaluate the previously proposed binding conformations such as alpha-helix and antiparallel beta-sheets. This shows that the previously reported conformations do not satisfy the experimental data. A new binding conformation of Ac-BB[7-14] is proposed consisting of three consecutive gamma-turns followed by a bend and finishing with two gamma-turns. This low energy conformation (analogous to a fragment of thymidylate synthase, 2TSC) of bombesin stabilized by five internal hydrogen bonds, and with the side chains of residues Trp8 and Leu13 held on the same side of the peptide, is in agreement with the experimentally observed data. This and the results of molecular modelling may aid in the synthesis of conformationally restricted high affinity bombesin analogues and/or high affinity template-based GRP or NMB receptor agonists and antagonists.
 ...
PMID:Alanine scan and N-methyl amide derivatives of Ac-bombesin[7-14]. Development of a proposed binding conformation at the neuromedin B (NMB) and gastrin releasing peptide (GRP) receptors. 898 85

Prohormones such as the gastrin precursor can be phosphorylated at Ser residues, on passage along the secretory pathway. The phosphorylation site occurs in a sequence (-Ser-Ala-Glu-) that suggests these peptides are substrates for physiological casein kinase, but the presence of this enzyme in endocrine cells is unknown. We have examined the specificity of Golgi membrane kinases from lactating rat mammary gland, bovine adrenal medulla and the GH3 cell line, for phosphorylation of progastrin fragments and analogues. The kinetics of phosphorylation of peptides with the native sequence, -Arg-Arg-Ser-Ala-Glu- were similar to those of tryptic cleavage fragments (Ser-Ala-Glu-) in both mammary and endocrine cell preparations. The product of in vitro phosphorylation was chromatographically indistinguishable from native peptide. Peptides with the sequence Ser-Ala-Ala (i.e., substitution of Glu to Ala) were not phosphorylated. We conclude that a physiological casein kinase like enzyme can act on both the gastrin precursor and its COOH-terminal cleavage product, and occurs in the Golgi complex of both mammary gland and peptide-producing endocrine cells.
 ...
PMID:Phosphorylation of gastrin-related peptides: physiological casein kinase like enzyme in Golgi membranes from bovine adrenal chromaffin cells and GH3 cells. 909 53


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