Bioactivity of analogs of the N-terminal region of gastrin-17

Copps, Jeffrey; Ahmed, Shawn; Murphy, Richard F.; Lovas, Sándor

doi:10.1016/j.peptides.2009.09.012

Cited by 3 publications

(8 citation statements)

References 41 publications

(49 reference statements)

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“…However, this does not explain the inability of the G17(1-6) analog to activate the receptor. Results from studies both of biological activity and structure of the two peptides are similar aside from the results of proliferation assays and ECD studies [13, 15]. The slightly greater tendency of G17(1-6)-NH 2 to form helix/turn structure (as seen in the ECD studies) may be due to stabilization of the peptide structure by the C-terminal amide, and this structural difference, though not detectable by qualitative review of the VCD/IR spectra or REMD simulations, may account for the difference in activity.…”

Section: Discussionmentioning

confidence: 89%

“…The CDSSTR results, however, show that G17(1-6)-NH 2 has a greater percentage of helix/turn structure in these solvents than does G17(1-6) (Table 2). In lieu of other structural and binding differences, if indeed these conformational features represent the bioactive conformation of G17(1-6)-NH 2 , then they may be why G17(1-6)-NH 2 stimulates proliferation while G17(1-6) does not [13, 15]. …”

Section: Discussionmentioning

confidence: 99%

“…The distance between the alpha carbons of pGlu 1 and Trp 4 of the representative structure of cluster 1 is 0.77 nm in water and 0.87 nm in TFE for G17(1-4)-NH 2 and 0.8 nm in water and 0.84 nm in TFE for G17(1-4), again do not indicate type I/III β-turn [10]. These tetrapeptides, as well as the pentapeptides, can bind the receptor, most likely because they form some N-terminal β-turn structure, but they cannot activate the receptor, perhaps due to the lack of the glutamyl residue and C-terminal amide [15]. Also, the lesser tendency to form turn structures, as seen in the DSSP plots and the cluster 1 structures (Figure 8), probably accounts for the lower affinity of these short peptides for the G17-Gly receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Synthesis, cleavage, and purification of all analogs was conducted as described previously [15]. The identities of all purified peptides were verified by mass spectrometry using a Perkin Elmer ESI-MS quadrupole mass spectrometer.…”

Section: Methodsmentioning

confidence: 99%

“…It was also demonstrated that the N-terminal region of G17, G17(1-12), was able to stimulate the proliferation of HT-29 cells, showing that the C-terminal tetrapeptide (Trp-Met-Asp-Phe-NH 2 ) of G17 which is essential for binding and activation of the CCK2 receptor is not necessary for binding and activation of the putative G17-Gly growth promoting receptor [3]. Furthermore, we have shown [13] that 1, G17(1-12) binds to high and low affinity receptors on DLD-1 cells as does [Leu 15 ]G17-Gly and promotes the proliferation of such cells; 2, further excision of the sequence Glu 7 -Tyr 12 still gives a peptide, G17(1-6)-NH 2 , which binds, albeit with low affinity, and activates the putative growth promoting receptor on DLD-1 cells; 3, shorter N-terminal analogs with and without C-terminal amidation, including G17(1-6), bind with decreasing affinity than that of G17(1-6)-NH 2 [15]. Sequences shorter than G17(1-4) fail to stimulate proliferation of DLD-1 cells.…”

Section: Introductionmentioning

confidence: 99%

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The structure of bioactive analogs of the N-terminal region of gastrin-17

2009

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Gastrin-17 (G17) processing intermediates bind to non-CCK receptors which mediate growth of the colonic mucosa but also the formation and development of colonic cancers. In previous studies, we removed the C-terminal region of G17 to form G17(1-12) and considerably shorter C-terminally amidated and non-amidated analogs. Peptides as short as G17(1-4) continued to bind to a single site on DLD-1 human colonic carcinoma cells, while only the G17(1-6)-NH 2 and G17(1-12) peptides retained the ability to activate the receptor and stimulate cell proliferation in vitro. In this report, we studied the structure of these analogs, using a combination of ECD and VCD spectroscopy and replica exchange Molecular Dynamics (REMD) simulations in water, TFE, and membrane-mimicking environments, in order to determine preferred conformations that may have importance in promoting the biological activities. Mostly random meander structures, punctuated by a β-turn at residues 1-4, were found in most peptides by REMD simulations. G17(1-3)-NH 2 , which cannot form a β-turn, failed to bind the non-CCK receptor, suggesting the importance of this feature for binding. Additionally, the β-turn appeared more frequently longer sequences, perhaps explaining the higher affinity of the non-CCK receptor for these peptides seen previously. Finally, C-terminally amidated peptides generally showed greater formation of turn structure than their non-amidated counterparts as shown ECD spectra, suggesting the importance of peptide length in stabilizing turn structure in N-terminal sequences, and perhaps explaining the ability of G17(1-6)-NH 2 to activate the non-CCK receptor where as the non-amidated G17(1-6) and shorter peptides do not.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The structure of bioactive analogs of the N-terminal region of gastrin-17

2009

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2011

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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The Production and Role of Gastrin-17 and Gastrin-17-Gly in Gastrointestinal Cancers

Copps

Murphy

Lovas³

2009

PPL

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The gastrointestinal peptide hormone gastrin is responsible for initiating the release of gastric acid in the stomach in response to the presence of food and/or humoral factors such as gastrin releasing peptide. However, it has a role in the growth and maintenance of the gastric epithelium, and has been implicated in the formation and growth of gastric cancers. Hypergastrinemia resulting from atrophic gastritis and pernicious anemia leads to hyperplasia and carcinoid formation in rats, and contributes to tumor formation in humans. Additionally, gastrin has been suspected to play a role in the formation and growth of cancers of the colon, but recent studies have instead implicated gastrin processing intermediates, such as gastrin-17-Gly, acting upon a putative, non-cholecystokinin receptor. This review summarizes the production and chemical structures of gastrin and the processing intermediate gastrin-17-Gly, as well as their activities in the gastrointestinal tract, particularly the promotion of colon cancers. Gastrin processing in the GI tractJohn Sydney Edkins postulated in 1905 [1][2] that the acid secretory activity of the stomach could be attributed to the agent gastrin. The gastrin gene is expressed and gastrin secreted in a variety of cells in the body, among them those of the small and large intestine (duodenal, jejunal, ileal, and colonic mucosas), the pancreas, neuroendocrine tissue (the pituitary and hypothalamus, cerebellum, vagal nerve, and adrenal medulla), the genitals and the respiratory tract, where it serves a variety of purposes [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. However, "mature" gastrin is predominantly manufactured by the antral mucosa of the stomach, where G endocrine cells secrete the peptide in response to the presence of amino acids, dietary amines, and calcium in the stomach, for the purpose of stimulating gastric acid secretion [19-25, reviewed in 26]. Neutralization of acid or inhibition of acid secretion also stimulates gastrin release [27][28][29][30][31][32][33]. In addition to luminal stimuli, basolateral stimuli of the G cells by GRP or Ach from nerve fibers, or by humoral factors such as EGF, also cause the expression and secretion of gastrin in some species [34][35]. In response to increased acid levels or VIP, D endocrine cells, in turn, secrete somatostatin, which acts to inhibit the secretion of gastrin.The expression of the gastrin gene and the processing of its polypeptide product in the gastrointestinal tract have been gradually revealed through extraction from gastrin-producing tissues and characterization of its processing intermediates with antibodies, chromatography and peptide analysis tools such as mass spectrometry. Genomic DNA information revealed the gastrin gene structure. The mRNA of the 101-residue gastrin precursor preprogastrin is translated at the endoplasmic reticulum, where an N-terminal signaling sequence is cleaved *Corresponding author: Sándor Lovas, Department of Biomedical Sciences, Creighton University School of Medi...

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Bioactivity of analogs of the N-terminal region of gastrin-17

Cited by 3 publications

References 41 publications

The structure of bioactive analogs of the N-terminal region of gastrin-17

The structure of bioactive analogs of the N-terminal region of gastrin-17

Current World Literature

The Production and Role of Gastrin-17 and Gastrin-17-Gly in Gastrointestinal Cancers

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