Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The octacosapeptide sequence [Tyr18] pro-ocytocin/neurophysin (1-18)NH2 [pro-OT/Np(1-18)NH2] was synthesized and used as substrate to detect endoprotease(s) possibly involved in the processing of this precursor in bovine hypothalamo-neurohypophyseal tract. An endopeptidase (58 Kda) was detected in Lysates made from highly purified neurosecretory granules. This protease which cleaves the peptide bond on the carboxyl side of the Lys-Arg doublet, and no single basic residue, generates both OT-Gly10-Lys11-Arg12+Ala13-Val-Leu-Asp-Leu-Tyr18 (NH2) from the octacosapeptide substrate. In addition, a carboxypeptidase B-like activity converting OT-Gly10-Lys11-Arg12 into OT-Gly10 was detected in the same granule Lysates. It is hypothesized that a combination of these endoprotease and carboxypeptidase B-like activities together with the amidating enzyme of secretory granules might participate in the cleavage and processing of pro-OT/Np in vivo.
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PMID:An endopeptidase associated with bovine neurohypophysis secretory granules cleaves pro-ocytocin/neurophysin peptide at paired basic residues. 351 14

Proline endopeptidase (E.C.3.4.21.26) is an enzyme which cleaves several neuropeptides at the carboxyl-side of proline residues. Some peptide substrates of this enzyme may be found in the rat hypothalamus (thyrotropin releasing hormone, neurotensin, substance P, oxytocin, vasopressin, beta-endorphin). Recent research has shown that the hypothalamic levels of some of these substances (e.g., vasopressin, beta-endorphin) change by a variety of training procedures. We studied the effect of various forms of training on the activity of proline endopeptidase of rat hypothalamus. The present results show that the activity of this enzyme is not altered by electroconvulsive shock or inhibitory avoidance training when measured, 0, 1, or 3 hr after these procedures. Other behavioral procedures (habituation to an open field, two-way active avoidance conditioning, or 1 min of inescapable footshock) also had no effect on hypothalamic proline endopeptidase activity measured immediately after training or test sessions. We conclude that proline endopeptidase probably does not play a regulatory role in the effect of synaptically released hypothalamic neuropeptides on behavior.
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PMID:Hypothalamic proline endopeptidase activity is not changed by various behavioral procedures. 353 16

Vasoactive peptides contain a high proportion of proline residues which make them resistant to hydrolysis by many peptidases. However, post proline cleaving enzyme (PPCE; EC 3.4.21.26), a proline specific endopeptidase which specifically hydrolyzes internal peptide bonds on the carboxyl side of proline residues, has been shown to inactivate numerous vasoactive peptides including angiotensins, kinins, substance P, vasopressin and oxytocin. In order to determine whether PPCE could be involved in vascular metabolism of vasoactive peptides, we carried out localization and characterization studies of PPCE-like activity in hog aorta and mesenteric artery. PPCE was assayed fluorometrically at pH 7.0 using the specific PPCE substrate CBZ-Gly-Pro-4-methyl-coumarinylamide. The subcellular distribution of vascular PPCE was essentially the same as that of the cytosolic marker enzyme lactic dehydrogenase (LDH). PPCE was enriched six-fold in the cytosolic fraction (11.4 +/- 2.7 units/mg) and unlike the plasma membrane-bound proline specific exopeptidase dipeptidyl-(amino)peptidase IV (DAP IV; EC 3.4.14.5), little or no activity could be detected in the microsomal or plasma membrane fractions. Similar to PPCE characterized from other sites, vascular PPCE was stabilized and activated by dithiothreitol and EDTA, and inhibited by DFP, p-chloromercuriphenyl sulfonic acid, L-1-tosylamido-2-phenylethylchloromethyl ketone, Cu++, Ca++, and Zn++. Vascular PPCE was unaffected by inhibitors of trypsin and kallikrein (Aprotinin, ABTI), aminopeptidase M (bestatin, amastatin), neutral endopeptidase (phosphoramidon), angiotensin I converting enzyme (captopril) or carboxypeptidase N (MERGETPA). These data demonstrate that PPCE is present in vascular endothelium and/or smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular, post proline cleaving enzyme: metabolism of vasoactive peptides. 354 18

The guinea pig two-domain precursor of MSEL-neurophysin and copeptin has been passed through a trypsin-Sepharose column in order to mimic the enzyme processing by a membrane-bound endopeptidase. Only two cleavages were observed located in the inter-domain sequence (at Arg-94 and Arg-98), in contrast to several additional cleavages found when free neurophysin or copeptin is subjected to soluble trypsin. Because the physiological maturation involves a single cleavage at Arg-94, both local accessibility in the precursor and narrow specificity of the enzyme are implied in the processing.
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PMID:Conformation limited proteolysis in the common neurophysin-copeptin precursor shown by trypsin-sepharose chromatographic proteolysis. 359 48

Microvilli from human placental syncytiotrophoblast are rich in angiotensin I converting enzyme (ACE), aminopeptidase A, a carboxypeptidase N-like enzyme, and a neutral endopeptidase (NEP). The specific activities of these enzymes were enhanced in microvillus-enriched fractions obtained by differential centrifugation: Purified microvilli were isolated in a discontinuous sucrose gradient. The placental microvilli hydrolyzed angiotensin II, vasopressin and oxytocin as shown by high pressure liquid chromatography. The inhibitors, bestatin, phosphoramidon, and o-phenanthroline, established the specificity of the enzymes. Aminopeptidase A (angiotensinase A) cleaved angiotensin II to angiotensin III and Asp1. NEP from placenta and from human kidney hydrolyzed oxytocin at the Pro7-Leu8 bond to yield oxytocin 1-7 and leucyl-glycine amide, but did not hydrolyze vasopressin. Vasopressin was cleaved by aminopeptidases in the placental membranes. On electroblotting placental NEP appeared as a double band with a molecular weight slightly higher than the 90,000 of the purified kidney enzyme. Neuraminidase treatment reduced the molecular weight of the placental enzyme to approximately 90,000, indicating that it contains a large amount of sialic acid. The microvilli of human placenta are thus rich in enzymes that may regulate passage of peptides at the maternal-fetal interface.
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PMID:Enzymes in placental microvilli: angiotensin I converting enzyme, angiotensinase A, carboxypeptidase, and neutral endopeptidase ("enkephalinase"). 609 76

Previous studies have shown that a neutral metallo-endopeptidase purified from rat kidney degrades the B chain of insulin, glucagon, ACTH and, at a markedly slower rate, the A chain of insulin. In contrast the enzyme does not attack native insulin, oxytocin, vasopressin, ribonuclease, albumin or denatured hemoglobin. The current studies demonstrate that the neutral peptidase also degrades the isolated C-peptide of proinsulin and cleaves certain peptide bonds in and near the C-peptide moiety of native proinsulin. Time courses of the formation of fluorescamine-reactive material during digestion of proinsulin and isolated C-peptide with the peptidase were identical. However, structural analysis of the peptidase-digested proinsulin showed that the enzyme does not convert proinsulin to insulin but that the peptidase cleaves one bond, Tyr26-Thr27, in the B chain moiety and five bonds in the C-peptide moiety, producing four split proinsulins. One of the split proinsulins is des-octacosa-peptide (27-54) porcine proinsulin or des-tetracosapeptide (27-50) bovine proinsulin. Each is a derivative of the insulin molecule having an extension of nine residues (ten residues in the case of the derivative from bovine proinsulin) at the N-terminus of A chain and lacking four residues at the C-terminus of B chain. This two chain derivative retains full immunoreactivity with insulin antibodies and exhibits 2.4-times more biological activity (promotion of glycogenesis in primary cultured hepatocytes) than proinsulin and about two-thirds the activity of insulin.
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PMID:Degradation of proinsulin and isolated C-peptide by rat kidney neutral metallo-endopeptidase. 702 23

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

Neutral endopeptidase (NEP; EC 3.4.24.11), an enzyme which metabolizes several peptides (including oxytocin and endothelins) implicated in the control of uterine function, was found to be localized in the ovine uterus throughout the oestrous cycle and in the uterus and conceptus during early pregnancy, using immunohistochemical techniques. Positive NEP immunoreactivity was found in the endometrium principally in stromal cells, in the vasculature in endothelial and vascular smooth muscle cells, and also weakly in some glandular epithelial cells. In a layer of stromal fibroblasts several cells in thickness underlying the luminal epithelium, staining was much weaker than that in the deeper stromal cells throughout the period examined. NEP staining was also present in smooth muscle cells of the myometrium at all times, and was most intense in the layer of cells adjacent to the endometrium. In the conceptus, NEP immunohistochemical staining was found in uninucleate cells, but not in binucleate trophoblast cells, in epithelial cells of the allantois and amnion, and in the heart and brain of the Day-20 embryo. In ovariectomized ewes treated with oestrogen or progesterone separately or remaining untreated, immunohistochemical staining of NEP was stronger when compared with intact ewes, in caruncular and intercaruncular stroma and epithelia, in glands, in the vasculature and in myometrium. The staining was less intense in all cell types in ewes receiving oestrogen plus progesterone. The expression of NEP and its specific regionalization within the uterus indicate a mechanism by which the availability of biologically important peptides involved in the regulation of the oestrous cycle and implantation, including oxytocin and endothelin, can be controlled by regulation of their metabolism.
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PMID:Localization of neutral endopeptidase in the ovine uterus and conceptus during the oestrous cycle and early pregnancy. 756 53

Oxytocin (OT) synthesized within human decidua may influence the timing of human parturition. Metabolism of OT within intrauterine tissues may regulate local concentrations. We hypothesized that a decrease in OT metabolism may contribute to an increase in local tissue concentrations around the time of parturition. Thus, we compared OT degradation in human decidua with that in chorion and placenta obtained before or after labor onset at term. We measured kinetic parameters for OT metabolism and determined pathways of degradation. Both cytosol and microsomal fractions contained aminopeptidase and postproline endopeptidase activities. Metabolism in the microsomal fractions was predominantly by an aminopeptidase enzyme that cleaves the ring structure of OT and removes amino acid residues from the N-terminal end. Metabolism in the cytosol fractions was predominantly via postproline endopeptidase activity, which cleaves the C-terminal Leu8-Gly9NH2. The resultant OT-(1-7) also is a substrate for aminopeptidase activity. The apparent maximum velocities of OT metabolism in the cytosol subcellular fractions of decidua (0.87 +/- 0.30 nmol/mg protein.min) and chorion (1.04 +/- 0.47) were significantly (P < or = 0.05) higher than those in corresponding microsomal fractions (0.17 +/- 0.05 and 0.29 +/- 0.10, respectively). Placental cytosols (1.08 +/- 0.34) were similar to decidua and chorion, but the microsomal fractions had significantly greater activity (0.82 +/- 0.22). The Km values for all tissues were in the range of 8-20 mumol/L. There were no significant changes in the kinetic parameters for OT metabolism around the time of labor onset. We conclude that human decidua and chorion as well as placenta actively metabolize OT, but changes in metabolism do not occur around parturition. If increasing decidual concentrations of OT play a role in the timing of human labor onset, mechanisms that increase production or secretion are of primary importance.
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PMID:Metabolism of oxytocin in human decidua, chorion, and placenta. 767 16

Oxytocin proteolysis was studied in vitro with purified synaptic membranes and in vivo after injection into the hippocampus of male Wistar Kyoto rats of different ages. When oxytocin was incubated in vitro with brain synaptic membranes obtained from 2-, 6-, and 12-month-old rats, no difference in the content of C-terminal and N-terminal fragments formed by membrane-bound aminopeptidase-like and endopeptidase-like enzymes, respectively, was found after high performance liquid chromatography separation and quantification by amino acid analysis. In contrast, the content of all fragments decreased by about 20%-25% when membranes obtained from 18- and 24-month-old rats were used. When [3H-Tyr2]oxytocin was injected in vivo in the hippocampus of 2-, 6-, 12-, and 18-month-old rats, no difference in the content of free [3H]-tyrosine and other [3H]-labelled fragments was found in the hippocampal peptidic extract after high performance liquid chromatography fractionation. However, the content of all radioactive fragments was about 50% lower in the extract from 24-month-old rats. The findings suggest that oxytocin proteolysis in brain decreases during aging. Such a decrease might counterbalance the impairment of central oxytocinergic transmission caused by the age-related decrease of oxytocin content in brain.
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PMID:Brain proteolysis of oxytocin in vitro and in vivo changes during aging in male rats. 783 89


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