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)

A bovine brain thyrotropin-releasing-factor (thyroliberin) deamidase has been purified 1100-fold to apparent homogeneity. Molecular weight estimates by gel filtration and sodium dodecylsulfate gel electrophoresis indicate that the enzyme consists of a single polypeptide chain of molecular weight of about 62 000-65 000. The enzyme is inactivated by sulfhydryl blocking agents. Serine proteinase inhibitors, phenylmethanesulfonyl fluoride and benzamidine, have no effect. Besides thyroliberin, the enzyme hydrolyzes peptide bonds involving the carboxyl group of proline residues in luliberin, tuftsin, angiotensin II, melanotropin, and neurotensin. Oxytocin, vasopressin, and bradykinin are not cleaved; they are, however, strong competitive inhibitors of thyroliberin deamidation. The specificity studies indicate that the enzyme is a "post-proline cleaving enzyme" which hydrolyzes peptides of the general structure, Yaa-Pro-Xaa, in which Xaa = amino acid, peptide, or amide (not Pro), and Yaa = N-blocked basic amino acid or a peptide sequence in which the C-terminal residue (i.e. the residue prior to Pro) is a basic amino acid such as His, Lys, or Arg. The enzyme is compared to other post-proline cleaving enzymes.
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PMID:Purification and properties of a bovine brain thyrotropin-releasing-factor deamidase. A post-proline cleaving enzyme of limited specificity. 679 65

An endo-acting proline-specific oligopeptidase (prolyl oligopeptidase [POPase], EC 3.4.21.26) was purified to homogeneity from the Triton X-100 extracts of cells of Treponema denticola ATCC 35405 (a human oral spirochete) by a procedure that comprised five successive fast protein liquid chromatography steps. The POPase is a cell-associated 75- to 77-kDa protein with an isoelectric point of ca. 6.5. The enzyme hydrolyzed (optimum pH 6.5) the Pro-pNA bond in carbobenzoxy-Gly-Pro-p-nitroanilide (Z-Gly-Pro-pNA) and bonds at the carboxyl side of proline in several human bioactive peptides, such as bradykinin, substance P, neurotensin, angiotensins, oxytocin, vasopressin, and human endothelin fragment 22-38. The minimum hydrolyzable peptide size was tetrapeptide P3P2P1P'1, while the maximum substrate size was ca. 3 kDa. An imino acid residue in position P1 was absolutely necessary. The hydrolysis of Z-Gly-Pro-pNA was potently inhibited by the following, with the Ki(app) (in micromolar) in parentheses: insulin B-chain (0.7), human endothelin-1 (0.5), neuropeptide Y (1.7), substance P (32.0), T-kinin (4.0), neurotensin (5.0), and bradykinin (16.0). Chemical modification and inhibition studies suggest that the POPase is a serine endopeptidase whose activity depends on the catalytic triad of COOH ... Ser ... His but not on a metal. The amino acid sequence around the putative active-site serine is Gly-Gly-Ser-Asn-Pro-Gly. The enzyme is suggested to contain a reactive cysteinyl residue near the active site. Amino acid residues 4 to 24 of the first 24 N-terminal residues showed a homology of 71% with the POPase precursor from Flavobacterium meningosepticum and considerable homology with the Aeromonas hydrophila POPase. The ready hydrolysis of human bioactive peptides at bonds involving an imino acid residue suggests that enzymes like POPase may contribute to the chronicity of periodontal infections by participating in the peptidolytic processing of those peptides.
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PMID:An endo-acting proline-specific oligopeptidase from Treponema denticola ATCC 35405: evidence of hydrolysis of human bioactive peptides. 752 1

Lactation is associated with complex changes of the hypothalamo-neurohypophysial system, and oxytocin released within the hypothalamic supraoptic (SON) and paraventricular nuclei may serve as a signal of communication between the magnocellular nuclei in lactating rats. In the first study, the intranuclear and peripheral release patterns of oxytocin and vasopressin in response to intraperitoneal hypertonic saline were studied in virgin and lactating rats to determine if the reduced osmoresponsiveness of the oxytocinergic and vasopressinergic systems during lactation is reflected by reduced release not only into blood, but also within the SON. Simultaneous microdialysis was performed within the SON and the jugular vein before and up to 6 hr after peripheral osmotic stimulation (3.0 M NaCl, 0.6 ml/100 gm body weight, i.p.). There was an immediate increase in secretion of both oxytocin and vasopressin into blood, whereas peptide release within the SON was delayed and peaked after 4-5 hr. Peripheral release of both peptides was significantly reduced in lactating animals, whereas within the SON release of oxytocin, but not vasopressin, was significantly reduced during lactation. In the second study, cross talk between the SONs--another phenomenon which seems to be characteristic for lactation--was studied. Microdialysis of one SON with hypertonic perfusion medium (with 1 M NaCl) significantly increased the release of oxytocin, vasopressin, and various amino acids (aspartate, glutamate, serine, glutamine, gamma amino butyric acid, and arginine) within the ipsilateral SON. In contrast to virgin female and male animals, this unilateral stimulation of the SON resulted in a transiently increased release of oxytocin in the contralateral SON of lactating rats. The release of vasopressin and amino acids within the contralateral SON of lactating rats remained unchanged, indicating specific activation of contralateral oxytocinergic neurons.
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PMID:Osmotic responsiveness and cross talk involving oxytocin, but not vasopressin or amino acids, between the supraoptic nuclei in virgin and lactating rats. 775 20

To study the oxytocic effect of trypsin, we measured the force of isometric contraction in uteri isolated from estrogenized rats exposed to trypsin (8.8 x 10(-10) to 1.7 x 10(-6) mol/L) either alone or in the presence of receptor antagonists to angiotensin II [saralasin ([Sar1,Ala8]angiotensin II) or DuP 753 (losartan)] or to kinins (D-[Arg0,Hyp3,Thi5,8,D-Phe7]-bradykinin). We found that saralasin or DuP 753, but not the kinin antagonist, displaced the dose-response curve to the right. Exposure to exogenous angiotensin I desensitized the preparation to further doses of either angiotensin I or II or trypsin, without altering the effects of oxytocin or bradykinin. Enalaprilat (an angiotensin I converting enzyme inhibitor) or pepstatin A (a renin inhibitor) also displaced the dose-response curve to trypsin to the right, without altering the effects of oxytocin or angiotensin II. Our results indicate that the response to trypsin is mediated by an agent produced from a substrate present in the uterus and acting on the angiotensin II type 1 receptor and are consistent with both renin and angiotensin I converting enzyme being involved in its mechanism of action, thus supporting the notions that the renin-angiotensin system may be important in the late stages of pregnancy and that serine proteases existing in the uterus may contribute to its activation.
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PMID:Oxytocic effect of trypsin on the isolated rat uterus. 828 69

Neurophysin is an allosteric protein in which peptide binding and self-association are positively linked. Reaction of neurophysin with succinic anhydride led to a large decrease in peptide affinity assignable to succinylation of a serine or threonine hydroxyl group. To identify the residue involved, acetimidated protein was reacted with [14C]succinic anhydride and the active and inactive components were separated by affinity chromatography. Performic acid oxidation and tryptic and Asp-N mapping of the two components, followed by automated Edman degradation, allowed identification of the critical residue as Ser-56. This residue is not a direct participant in peptide binding and is distant from the subunit interface of the dimer, but it is immediately adjacent to the site of one of the known mutations associated with familial diabetes insipidus. Examination in solution of the peptide affinity of neurophysin succinylated at Ser-56 indicated a binding affinity approximately 1/20th that of the native protein or of protein succinylated at other residues, and a loss of the normal dependence of binding affinity on protein concentration. Under the same buffer conditions, loss of the concentration dependence of binding, in addition to the previously demonstrated loss of binding affinity, also accompanied excision of residues 1-8, an effect attributed to the loss of binding site residue Arg-8. However, in contrast to the effects of succinylation on native neurophysin, only minor effects of succinylation on the binding affinity of the des-1-8 protein were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of allosteric interactions in neurophysin induced by succinylation of serine-56 or cleavage of residues 1-8. 839 21

Excitatory amino acid (EAA) neurotransmitters participate in the regulation of secretion of several neuropeptides, including oxytocin (OT), via actions at different receptors. In earlier studies, release of OT could be achieved reliably by injection into the supraoptic nucleus (SON) of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor agonists, but not by treatment with N-methyl-D-aspartate (NMDA) alone. This prompted further examination of the possible role of NMDA receptors in OT release following central coapplication of NMDA and AMPA-site agonists, or of NMDA and agonists active at the glycine coagonist site. The agonists were injected into the right SON, the right paraventricular nucleus (PVN), or into the third ventricle (3V) of nonsuckled lactating rats. Cotreatment with NMDA and AMPA (using doses that alone did not include OT release) elicited a strong OT release in all animals by either the SON or the PVN route, and this was attenuated by pretreatment/cotreatment with specific antagonists of either the NMDA or the AMPA receptor. The SON area or 3V coinjection of NMDA and the NMDA/glycine site agonists glycine or D-serine also induced OT discharges in all animals, while cotreatment in the PVN did not result in uniform OT discharges. This release was potently reduced by cotreatment with the specific NMDA/glycine site antagonist 5, 7-dichlorokynurenate (DCK). L-Serine somewhat increased the frequency of discharge-type response to NMDA, while intra-SON coinjection of L-leucine did not stimulate OT release. D-Serine alone stimulated the release of OT much less than in combination with NMDA, and with no obvious dose dependence. The suckling-induced release of OT was attenuated, but not abolished, by DCK, while PRL release was briefly stimulated by this agent. A physiological role for the NMDA receptor in OT release is clearly supported by these studies. NMDA receptor activation in the lactating rat may result from either an allosteric stimulation by glycine site agonists, or a synergistic interaction with the AMPA/kainate group of excitatory amino acid receptors.
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PMID:Central stimulation of oxytocin release in the lactating rat by N-methyl-D-aspartate: requirement for coactivation through non-NMDA glutamate receptors or the glycine coagonist site. 855 78

Proteolytic enzymes, which are synthesized and secreted by cells of the seminiferous tubule of the testis, have important functions in spermatogenesis. We performed metabolic studies using small peptide hormones as a substrate to investigate the activity of proteases in cultured Sertoli cells of the rat. High-performance liquid chromatographic analysis of the cell culture supernatants showed cleavage of met- and leu-enkephalin, substance P, and bradykinin. No peptidolysis was observed for the cyclic peptide oxytocin. The hormone cleavage pattern and the use of specific protease inhibitors in peptide degradation experiments demonstrated activities of several proteases in Sertoli cells. These are mainly metalloproteinases including neutral metalloendopeptidases, angiotensin-converting enzyme and aminopeptidases. In addition, activities of serine and aspartic proteases were detected. Only marginal proteolytic activities were observed in Sertoli cell conditioned supernatants, indicating that the investigated proteases are mainly located on Sertoli cell membranes. The peptide hormones used in this study have been found to play a potential role in the endocrine, paracrine or autocrine regulation of testicular cells. The membrane-associated proteases reported here may therefore be involved in the metabolism and inactivation of these peptides.
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PMID:Possible involvement of proteases in the regulation of spermatogenesis. 973 15

Familial diabetes insipidus (FDI) is a syndrome of central vasopressin deficiency that is inherited in an autosomal dominant manner and that typically becomes clinically apparent in the first decade of life. Two novel mutations of the vasopressin gene have been identified in two previously unstudied kindreds with FDI. In each kindred, the inheritance of the FDI phenotype was consistent with an autosomal dominant mode of inheritance. In each proband, the diagnosis of central diabetes insipidus had been confirmed previously with a water deprivation protocol. After extraction of genomic DNA from each individual, the three exons of the vasopressin gene were separately amplified by PCR and directly sequenced using an automated dye termination method. In the proband and two other carriers of one kindred, a heterozygous C to T mutation was identified at nucleotide 1857. This is predicted to produce a serine to phenylalanine substitution at residue 56 of the vasopressin-related neurophysin peptide encoded by the mutated allele. The mutation also abolished an MspI site in the vasopressin sequence, and analysis of genomic DNA from eight members of the kindred (five with FDI) confirmed segregation of the mutation with the FDI phenotype. Another member of the kindred, a 13-month-old infant, also has the heterozygous C to T mutation, but a formal water balance study showed no evidence of diabetes insipidus. In the proband of the other kindred, a heterozygous G to A mutation was identified at nucleotide 1873. This mutation would be predicted to cause a cysteine to tyrosine substitution at residue 61 of the neurophysin encoded by the mutated allele. This heterozygous mutation was confirmed by the presence of an RsaI restriction site in one vasopressin allele in two members of the kindred. Therefore, two novel heterozygous mutations of the vasopressin gene have been identified in FDI kindreds. In one kindred, an asymptomatic carrier infant was identified and will require continued observation to determine whether she will develop clinical diabetes insipidus. The presence of these two novel mutations in a region of the vasopressin gene where other FDI mutations have been reported suggests that the part of the neurophysin peptide encoded by these sequences may be critically important in the appropriate expression of vasopressin.
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PMID:Two novel mutations of the vasopressin gene associated with familial diabetes insipidus and identification of an asymptomatic carrier infant. 981 75

Autosomal dominant neurohypophyseal diabetes insipidus is caused by mutations in the gene encoding the vasopressin precursor protein, prepro-vasopressin-neurophysin II. We analyzed the molecular consequences of a mutation (DeltaG227) recently identified in a Swiss kindred that destroys the translation initiation codon. In COS-7 cells transfected with the mutant cDNA, translation was found to initiate at an alternative ATG, producing a truncated signal sequence that was functional for targeting and translocation but was not cleaved by signal peptidase. The mutant precursor was completely retained within the endoplasmic reticulum. The uncleaved signal did not affect folding of the neurophysin portion of the precursor, as determined by its protease resistance. However, formation of disulfide-linked aggregates indicated that it interfered with the formation of the disulfide bond in vasopressin, most likely by blocking its insertion into the hormone binding site of neurophysin. Preventing disulfide formation in the vasopressin nonapeptide by mutation of cysteine 6 to serine was shown to be sufficient to cause aggregation and retention. These results indicate that the DeltaG227 mutation induces translation of a truncated signal sequence that cannot be cleaved but prevents correct folding and oxidation of vasopressin, thereby causing precursor aggregation and retention in the endoplasmic reticulum.
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PMID:Mechanism of endoplasmic reticulum retention of mutant vasopressin precursor caused by a signal peptide truncation associated with diabetes insipidus. 1038 95

The hot methanol extract (HME) of Monechma ciliatum which has been reported to have potent oxytocic activity was purified by fractionation in an attempt to isolate the oxytocic principle. Thin layer analysis indicated that the oxytocic fraction was very polar. A positive reaction with ninhydrin-spray suggested that it is an amino acid/protein. Repeated column chromatography (CC) on silica gel followed by sephadex LH-20 column, accompanied by bioassay of the fractions on the rat isolated uterus enabled partial isolation of the oxytocic principle (P3) to be achieved. Although the exact structure of P3 could not be identified from the present study, various spectral analyses suggest that it is a small peptide made up of tyrosine, leucine and a third component which is probably serine. It is interesting to note that the parent compound, oxytocin, is also a peptide with tyrosine and leucine in its structure.
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PMID:Bioassay-directed isolation of oxytocic principles from the methanol extract of Monechma ciliatum. 1059 43

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