UNIPROT:P01178 - FACTA Search

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Query: UNIPROT:P01178 (oxytocin)
15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxytocin was synthesized via the solid-phase method using dehydroalanine as pseudo-protecting group of the carboxyl-terminal as well as the omega-amide functions of asparagine and glutamine in endo-position. Starting with Boc-Gly-Dha-resin and using Boc-L-Asp(Dha-NHEt)-OH and Boc-L-Glu(Dha-NHEt)-OH as precursors of asparagine and glutamine, respectively, oxytocin was assembled in stepwise manner under solid phase synthesis conditions. Treatment of the protected [Glu(Dha-NHEt)4, Asp(Dha-NHEt)5]-oxytocin-Dha-resin with 1 n HCl in glacial acetic acid in the presence of 3 equiv. water removed the peptide from the support with the simultaneous formation of the asparagine and glutamine residues to give the protected nonapeptide amide: Cbz-Cys(Bzl)-Tyr(Bzl)-Ile-Gln-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2, which was deprotected with sodium in liquid ammonia and then oxidized with diiodoethane to give oxytocin. After purification by gel chromatography and countercurrent distribution, the product displayed the chemical and physical properties and oxytocic activity (533 +/- 301U/mg) of a standard oxytocin preparation.
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PMID:Solid-phase synthesis of peptides via alpha, beta-unsaturated amino acids: oxytocin, simultaneous incorporation of amide functions in COOH-terminal and endo-positions. 711 12

Previous hydrodynamic studies [Rholam, M., & Nicolas, P. (1981) Biochemistry 20, 5837-5843] have demonstrated that the dimerization of a neurophysin monomer (prolate ellipsoid with an axial ratio, due to asymmetry, of 5.2) results in a decreased asymmetry (axial ratio, due to asymmetry, of 3.6) as the consequence of a side-by-side association process. By a combination of hydrodynamic measurements, including the use of sedimentation velocity, viscometry, and fluorescence polarization spectroscopy, the influence of hormone binding on the shape and asymmetry properties of the neurophysin dimer was evaluated. The binding of ocytocin, vasopressin, and the tripeptide analogue of the N-terminal sequence of ocytocin, Cys(S-Me)-Tyr-Ile-NH2, results in an increase of S020,W and a decrease in both the reduced viscosity and rotational relaxation time of the bis-liganded dimeric species vs. the nonliganded form. The axial ratio (a/b) due to asymmetry of the ligand-bound dimers was found in each case to be equal to, or slightly greater than, 1.0, indicating a compact spherical shape (Stokes radius 21 A). The profound alteration on molecular dimensions observed upon ligand binding is shown to be the consequence of a ligand-induced conformational change and might explain the intradimeric binding sites positive cooperativity. It is tentatively proposed that the pseudospherical shape of the neurophysin-hormone complexes may enhance the stability of neurophysin and contribute to the prevention of leakage of neuropeptides through the membrane of neurosecretory granules. The data provide a remarkable example of a small protein with a high content in disulfide links and that undergoes conspicuous changes in conformation under the influence of nonapeptide, or tripeptide, ligands.
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PMID:Binding of neurohypophyseal peptides to neurophysin dimer promotes formation of compact and spherical complexes. 713 41

[1-Penicillamine,2-leucine]oxytocin is a conformationally restricted analogue of oxytoxin in which the half-cystine-1 and tyrosine-2 residues of the native hormone are replaced by half-penicillamine (beta, beta-dimethyl-half-cystine) and leucine, respectively. This analogue is a surprisingly potent oxytocin antagonist [Hruby, V. J., Deb, K. K., Yamamoto, D. M., Hadley, M. E., & Chan, W. Y. (1979) J. Med. Chem. 22,7]. Extensive proton magnetic resonance experiments were performed to determine the conformational properties of this analogue in aqueous solution, and the results were compared with the previously published model for the conformation of [1-penicillamine]oxytocin. The results are consistent with a conformation similar to that of [1-penicillamine]oxytocin except that, while [1-penicillamine]oxytocin in aqueous solution possesses two 1 comes from 3 (C7) type turns involving the isoleucine-3 peptide amide proton and the half-penicillamine-1 carbonyl and the asparagine-5 peptide amide proton and the isoleucine-3 carbonyl, [1-penicillamine,2-leucine)oxytocin has only the latter 1 comes from 3 turn. This difference between the antagonists is reflected in the different phi and psi angles in the three N-terminal residues of the two inhibitor analogues and in differences in the preferred side-chain conformations for several residues. One particular result of these conformational differences is that, whereas for [1-penicillamine]oxytocin the tyrosine-2 side chain is unable to assume the rotamer for maximal binding to the uterine receptor, [1-penicillamine,2-leucine]oxytoxin retains conformational and dynamic properties at residues two and three which are more similar to those of oxytocin. It is postulated that these conformational and dynamic properties are consistent with the stronger binding and, hence, greater antagonist activity for this penicillamine analogue relative to [1-penicillamine]oxytocin.
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PMID:Conformational study of the potent peptide hormone antagonist [1-penicillamine,2-leucine]oxytocin in aqueous solution. 724 50

Earlier studies have shown the formation of a novel neural lobe after hypophysectomy, an experimental manipulation that causes transection of neurohypophyseal nerve fibers and removal of pituitary hormones. The mechanisms that underly this regenerative process are poorly understood. The localization and number of peptide-immunoreactive (-IR) fibers in the median eminence were studied in normal rats and in rats at different times of survival after hypophysectomy using indirect immunofluorescence histochemistry. The number of vasopressin (VP)-IR fibers increased in the external layer of the median eminence in 5 d hypophysectomized rats. Oxytocin (OXY)-IR fibers decreased in the internal layer and progressively extended into the external layer. At long survival times (9 and 16 months) both VP- and OXY-IR fibers had a bilayered distribution occupying both the external and internal layers. Double-labeling experiments combining VP and tyrosine hydroxylase antisera as well as OXY and growth hormone-releasing factor antisera showed that injured neurosecretory fibers growing into the external layer displaced fibers from parvocellular cells originally located there. As a result, there was essentially an inversion in the distribution of these fibers within the median eminence. Galanin (GAL)- and cholecystokinin (CCK)-IR fibers exhibited a similar pattern of distribution after the lesion. Thus, after 5 d there was an increase in GAL- and CCK-IR fibers in the internal layer. At 14 and 30 d, the number of GAL- and CCK-IR fibers progressively decreased, but after longer survivals (9 and 16 months) there was a dramatic reappearance. Dynorphin (DYN)-LI showed a dramatic increase at all levels of the median eminence at short survival times after hypophysectomy, followed by a subsequent decrease to a final stage of a few, strongly immunoreactive fibers in the external layer at longer survival times. Vasoactive intestinal polypeptide (VIP)- and peptide histidine-isoleucine (PHI)-IR fibers in hypophysectomized animals had already contacted portal vessels 5 d after hypophysectomy, and from then on progressively increased in numbers. Finally, most of the peptide fibers described above formed dense innervation patterns around the large blood vessels along the lateral borders of the median eminence. The present results show that hypophysectomy induces a wide variety of changes in hypothalamic neurosecretory fibers. Not only is the expression of several peptides in these fibers modified following different survival times, but a reorganization of the distribution of immunoreactive fibers within the median eminence is demonstrated. The hypothesis is raised that regeneration of injured neurosecretory fibers may be dependent on changes in the expression of peptides possessing trophic actions.
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PMID:Reorganization of neural peptidergic systems in the median eminence after hypophysectomy. 752 31

The expression of vgf gene, first isolated as a gene induced by nerve growth factor in PC12 cells, was investigated in neurons of the suprachiasmatic nucleus (SCN) by in situ hybridization. In the rat forebrain, the vgf mRNA was found most densely in the SCN. Neurons which express vgf mRNA were found both in the dorsomedial and ventrolateral subdivisions. Soluble-labeling of vgf in situ hybridization and peptide immunocytochemistry demonstrated that vgf mRNA was expressed in most vasopressin- and neurophysin-immunoreactive neurons in the dorsomedial part and in vasoactive intestinal peptide (VIP)- and peptide histidine isoleucine amide (PHI)-immunoreactive neurons in the ventrolateral part. These findings suggest that vgf is a highly expressed gene in both vasopressin/neurophysin neurons and VIP/PHI neurons which were speculated to be involved in the generation and entrainment of circadian rhythm.
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PMID:In situ hybridization histochemistry of vgf mRNA in the rat suprachiasmatic nucleus: co-localization with vasopressin/neurophysin and VIP/PHI. 771 6

The expression of vgf gene, first isolated as a gene induced by nerve growth factor in PC12 cells, was investigated in neurons of the suprachiasmatic nucleus (SCN) by in situ hybridization. In the rat forebrain, the vgf mRNA was found most densely in the SCN. Neurons which express vgf mRNA were found both in the dorsomedial and ventrolateral subdivisions. Double-labeling of vgf in situ hybridization and peptide immunocytochemistry demonstrated that vgf mRNA was expressed in most vasopressin- and neurophysin-immunoreactive neurons in the dorsomedial part and in vasoactive intestinal peptide (VIP)- and peptide histidine isoleucine amide (PHI)-immunoreactive neurons in the ventrolateral part. These findings suggest that vgf is a highly expressed gene in both vasopressin/neurophysin neurons and VIP/PHI neurons which were speculated to be involved in the generation and entrainment of circadian rhythm.
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PMID:In situ hybridization histochemistry of vghm1f mRNA in the rat suprachiasmatic nucleus: co-localization with vasopressin/neurophysin and VIP/PHI. 760 15

Several neuropeptides, including neurotensin, somatostatin, bradykinin, angiotensin II, substance P, and luteinizing hormone-releasing hormone but not vasopressin and oxytocin, were actively metabolized through proteolytic degradation by cultivated astrocytes obtained from rat cerebral cortex. Because phenanthroline was an effective degradation inhibitor, metalloproteases were responsible for neuropeptide fragmentation. Neurotensin was cleaved by astrocytes at the Pro10-Tyr11 and Arg8-Arg9 bonds, whereas somatostatin was cleaved at the Phe6-Phe7 and Thr10-Phe11 bonds. These cleavage sites have been found previously with endopeptidases 24.16 and 24.15 purified from rat brain. Addition of specific inhibitors of these proteases, the dipeptide Pro-Ile and N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-4-aminobenzoate, significantly reduced the generation of the above neuropeptide fragments by astrocytes. The presence of endopeptidases 24.16 and 24.15 in homogenates of astrocytes could also be demonstrated by chromatographic separations of supernatant solubilized cell preparations. Proteolytic activity for neurotensin eluted after both gel and hydroxyapatite chromatography at the same positions as found for purified endopeptidase 24.16 or 24.15. In incubation experiments or in chromatographic separations no phosphoramidon-sensitive endopeptidase 24.11 (enkephalinase) or captopril-sensitive peptidyl dipeptidase A (angiotensin-converting enzyme) could be detected in cultivated astrocytes. Because astrocytes embrace the neuronal synapses where neuropeptides are released, we presume that the endopeptidases 24.16 and 24.15 on astrocytes are strategically located to contribute significantly to the inactivation of neurotensin, somatostatin, and other neuropeptides in the brain.
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PMID:Endopeptidases 24.16 and 24.15 are responsible for the degradation of somatostatin, neurotensin, and other neuropeptides by cultivated rat cortical astrocytes. 790 52

In contrast to most vertebrate species that possess one oxytocin-like hormone and one vasopressin-like hormone, a few groups, such as marsupials or cartilaginous fishes, are endowed with two peptides of either or both types, suggesting possible gene duplications. We have now isolated two oxytocin-like hormones from the pituitary of the spotted dogfish Scyliorhinus caniculus (suborder Galeoidei). Microsequencing as well as chromatographic and pharmacological comparisons with synthetic peptides show that these peptides are [Asn4,Val8]oxytocin (asvatocin) and [Phe3,Asn4,Val8]-oxytocin (phasvatocin). Asvatocin and phasvatocin display oxytocic activity on rat uterus, about 80 and 5 milliunits per nmol, respectively, and virtually no pressor activity on anesthetized rats. They occur in roughly equal molar amounts in the gland; vasotocin is also present in a proportional amount that is lower by about a factor of 20. In addition to the duality, conservative amino acid substitutions are observed in the two oxytocic peptides in positions 4 (Gln-4-->Asn) and 8 (Leu-8-->Val), when compared with oxytocin. Furthermore, replacement of the isoleucine residue found in position 3 of all other oxytocin-like hormones by phenylalanine in phasvatocin is exceptional; it determines a dramatic decrease of the oxytocic activity. Preservation of the C-terminal-amidated nonapeptide pattern in the 12 vertebrate neurohypophysial hormones known to date suggests that both precursors and processing enzymes have coevolved tightly. On the other hand, whereas the great evolutionary stability of the mature hormones (generally observed in vertebrates) suggests a strict messenger-receptor coevolution, the exceptional diversity found in cartilaginous fishes (six oxytocin-like peptides identified out of eight known) might be due to a looseness of selective constraints, perhaps in relationship with their specific urea osmoregulation.
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PMID:Special evolution of neurohypophysial hormones in cartilaginous fishes: asvatocin and phasvatocin, two oxytocin-like peptides isolated from the spotted dogfish (Scyliorhinus caniculus). 797 45

In this study the interactions of oxytocin with the transmembrane region of the oxytocin receptor were modelled in order to explain the selective binding of oxytocin and vasopressin. Three sites of interaction in the receptors were identified by sequence comparison and model building. Both receptors share one site, which is formed by glutamine residues. This site binds the Asn-5 common to both hormones. The second site is a specific hydrophobic pocket formed by isoleucine and phenylalanine residues. A third interaction is between a conserved tyrosine and the glutamine of vasopressin and oxytocin. The model suggests that one receptor residue in the transmembrane region is responsible for the specificity of the receptors. The model may be used in the rational design of non peptide analogues for the hormones.
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PMID:Modelling the peptide receptor interaction: selectivity of the oxytocin receptor. 806 Mar 40

With the combined use of various two-dimensional (2D) NMR techniques, a complete assignment of the 1H and 13C resonances of oxytocin, Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2, for two molecular states, protonated and unprotonated at the N-terminal group, was performed in dimethyl sulfoxide. A small but distinct change in the backbone conformation of the six-residue cyclic moiety, associated with the protonation, was first suggested from those NMR parameters relevant to conformation, such as change with temperature in the chemical shifts of the peptide amide protons and changes in chemical shifts and homonuclear as well as heteronuclear three-bond coupling constants. The solution structures of oxytocin for the protonated and unprotonated forms were then calculated using distance analysis in dihedral-angle space, based on a relaxation matrix evaluated from quantitative NOE intensities at different mixing times. Total amounts of 93 and 105 distances were determined for the protonated and the unprotonated forms, respectively. There were 25 interresidue distances relevant to the structure of the cyclic moiety for the protonated form of oxytocin and 43 for the unprotonated form. Overall structures with the lowest target penalty function were similar between the two forms, having a beta-turn structure at the endocyclic residues of the Tyr-Ile-Gln-Asn moiety. The local backbone conformations near the N-terminus, however, were significantly different between the two forms. This was found to be due to a change in the dihedral angle of the disulfide bridge (chi ss around C-S-S-C), which closes the ring in the cyclic peptide. The dihedral angle was about +90 degrees for the unprotonated form and an intermediate value of about +45 degrees for the protonated form.
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PMID:Oxytocin solution structure changes upon protonation of the N-terminus in dimethyl sulfoxide. 811 Dec 31

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