Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatostatin (SRIF) is a putative peptide neurotransmitter that may interact with brain capillaries following neurosecretion of the peptide. The present studies investigate the binding and metabolism of SRIF analogues in isolated bovine brain microvessels. 125I-[Tyr1]SRIF was rapidly degraded by capillary aminopeptidase with a half-time of approximately 3 min at 23 degrees C. The microvessel aminopeptidase had a low affinity and high capacity for the peptide, Km = 76 microM and Vmax = 74 nmol min-1 mgp-1. 125I-[Tyr11]SRIF was converted to free iodotyrosine at a much slower rate, presumably by a lower-activity endopeptidase. 125I-[Try11]SRIF was rapidly bound by microvessels, whereas another basic peptide, [Tyr8]bradykinin, or an acidic peptide, CCK8, or a neutral peptide, leucine enkephalin, were bound to a considerably less extent. The binding of 125I-[Tyr11]SRIF to the capillaries was nonsaturable up to a concentration of 1 microgram/ml of unlabeled peptide, and the binding reaction was extremely rapid, reaching equilibrium within 5 s at either 0 degrees C or 37 degrees C. Approximately 20% of the SRIF bound by the microvessels was resistant to acid wash and presumably represented internalized peptide. In addition, the 125I-[Tyr11]SRIF bound rapidly to the endothelial cytoskeleton remaining after a 1% Triton X-100 extraction of the microvessels. The peptide-cytoskeletal binding reaction was nonsaturable up to 1 microgram/ml of unlabeled [Tyr11]SRIF, but it was inhibited by 0.5% polylysine or 0.8 M KCl and was stimulated by 1 mM dithiothreiotol. These studies suggest that brain microvessels rapidly sequester and degrade SRIF analogues and that this may represent one mechanism for rapid inactivation of the neuropeptides subsequent to neurosecretion.
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PMID:Rapid sequestration and degradation of somatostatin analogues by isolated brain microvessels. 285 72

Previous studies have shown that somatostatin-14 (S-14) is rapidly metabolized in the liver through the action of aminopeptidases and endopeptidases, resulting in separate cleavages at the N-terminus and the cyclized (ring) portion of the molecule. In the present study we have characterized the hepatic metabolism of somatostatin-28 (S-28) and compared it with that of S-14 to determine whether S-28 is degraded by a process similar to that for S-14, and additionally, whether the hepatic metabolism of S-28 results in significant conversion to S-14. Isolated rat livers were perfused with synthetic S-28, somatostatin-25[(S-25), an N-terminal metabolite of S-28], C- and N-terminally radioiodinated analogs of S-28, S-14, and des-Ala1-S-14[(S-13), an N-terminal metabolite of S-14]. The metabolic products were characterized by separate N-terminally directed S-14 and S-28 RIAs, a common ring-directed RIA for S-14, S-28, S-13, and S-25, immunoprecipitation, gel chromatography, and HPLC. Hepatic extractions of S-28 and S-25, monitored as ring-directed immunoreactivity, were equivalent, but both occurred 4 times more slowly than that of S-14 or S-13. By contrast, the N-terminal metabolism of S-14 and S-28 monitored by specific N-terminal RIAs occurred at similar rates (hepatic extraction of 54% and 44%, respectively). Both S-14 and S-28 were degraded significantly more rapidly at the N-terminus than at the ring segment. Immunochemical characterization of the radioactive metabolites of N- and C-terminally radioiodinated S-28 analogs confirmed the more rapid N-terminal cleavage of S-28 compared with its ring breakdown. Gel chromatography of S-28 perfusates followed by RIA of the column fractions for N-terminal and ring-reactive metabolites, showed a time-dependent conversion of S-28 to a peak coeluting with S-14 (27% conversion by 60 min). That S-14 was a significant metabolite of S-28 was further confirmed by HPLC analysis of the hepatic perfusate. The main hepatic metabolite of S-28 coeluted with S-28 on Sephadex columns but showed reduced N-terminal reactivity compared to intact S-28. This product thus appeared to be a N-terminally modified form of S-28 as also suggested by HPLC analysis where it coeluted with synthetic S-25. These data have demonstrated that the hepatic metabolism of S-28 occurs via three separate processes, two of which are similar to those for S-14. These include 1) endopeptidase cleavage through the cyclized (ring) segment; 2) N-terminal aminopeptidase cleavage to yield metabolites such as S-25; and 3) tryptic-like cleavage of the Arg-Lys region of S-28 to generate S-14.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hepatic metabolism of somatostatin-14 and somatostatin-28: immunochemical characterization of the metabolic fragments and comparison of cleavage sites. 286 Oct 82

The effects of somatostatin on cholera toxin-induced secretory diarrhea and the appearance of glycoenzymes in the intestinal lumen and intestinal lymph were investigated in rat small intestine. After exposure to cholera toxin, marked fluid accumulation in the small intestinal tract and elevation of the jejunal mucosal cyclic AMP (cAMP) concentration were observed. The activity of alkaline phosphatase, aminopeptidase and sucrase increased in the intestinal lumen after toxin exposure. In intestinal lymph, alkaline phosphatase activity was increased after cholera toxin administration, while aminopeptidase activity remained unchanged. Somatostatin suppressed cholera toxin-induced secretory diarrhea, but it did not affect the elevated mucosal cAMP concentration. This peptide also inhibited the appearance of glycoenzymes in the intestinal lumen and lymph induced by cholera toxin administration. These results suggest that somatostatin exerts its inhibitory effects on cholera toxin-induced secretory diarrhea and on the appearance of glycoenzymes in the intestinal lumen and lymph by affecting processes beyond cAMP formation.
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PMID:Inhibitory effect of somatostatin on cholera toxin-induced diarrhea and glycoenzyme secretion in rat intestine. 288 40

Two closely related Cl(-)-activated arginyl aminopeptidases (I and II) were purified from a soluble extract of postmortem human cerebral cortex by anion-exchange chromatography and preparative gel electrophoresis. The electrophoretic mobility of II was approximately 80% that of I; the molecular mass of both enzymes was approximately 70 kilodaltons (kDa) (gel filtration). The aminopeptidase action of I and II on aminoacyl-7-amido-4-methylcoumarin (AMC) substrates was restricted to the Arg and Lys derivatives. Both enzymes had significant endopeptidase activity, hydrolysing several biologically active peptides including neurotensin, bradykinin, angiotensin-I, substance P, luliberin, and somatostatin at internal bonds. Other peptides [Leu-enkephalin, proctolin, thyroliberin, adrenocorticotropin18-39 (ACTH18-39), ACTH11-24, and dynorphin (1-13)] were not appreciably hydrolysed. The amino- and endopeptidase activities had pH optima at 6.5 and 7, respectively, and were both inhibited by metal ion chelators and sulphydryl group blocking agents. The aminopeptidase activity was stimulated 20-fold by Cl- ions, whereas the endopeptidase activity was unaffected by the latter. Km values for neurotensin degradation were 20 microM (I) and 37 microM (II) and for Arg-AMC hydrolysis they were 167 microM (I) and 125 microM (II). The endopeptidase activity was not inhibited by the aminopeptidase inhibitors arphamenine or bestatin (IC50 = 9 nM and 0.1 microM, respectively, with Arg-AMC substrate).
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PMID:Purification and characterization of two soluble Cl(-)-activated arginyl aminopeptidases from human brain and their endopeptidase action on neuropeptides. 265 16

Rat brain aminopeptidase activity was solubilized from membranes by incubation with thiols. This novel procedure resulted in the release of the same two aminopeptidases (MI and MII) previously shown to be solubilized by the nonionic detergent Triton X-100. The solubilized aminopeptidases MI and MII were resolved by ion-exchange chromatography and further purified by hydroxylapatite chromatography. Aminopeptidase MI was shown to hydrolyze only the beta-naphthylamides of arginine and lysine whereas aminopeptidase MII exhibited a broad specificity with respect to amino acid beta-naphthylamides. Only aminopeptidase MII hydrolyzed Leu-enkephalin at a significant rate, indicating that this enzyme can account for the membrane-bound enkephalin aminopeptidase activity. The enkephalin-degrading aminopeptidase is potently inhibited by opioid (alpha-neo-endorphin and dynorphin) as well as nonopioid (substance P, somatostatin, and angiotensin I) peptides in the range of 0.2-2.0 microM. The regional distribution of aminopeptidases MI and MII in rat brain are rather different, with aminopeptidase MII distribution more closely paralleling the distribution of opiate receptors.
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PMID:Characterization of membrane-bound aminopeptidases from rat brain: identification of the enkephalin-degrading aminopeptidase. 388 43

Clearance of cyclic somatostatin (SRIF) from a plasma-free recirculating medium containing human erythrocytes and a bovine albumin fraction was measured with site-specific N-terminal (sheep B) and central core-directed (R101) radioimmunoassays during perfusion of the isolated rat liver (3-4 g). With the N-terminal radioimmunoassay (RIA), the t 1/2, hepatic clearance, and extraction of somatostatinlike immunoreactivity (SLI) were 20.9 +/- 2.0 (SE) min, 2.82 +/- 0.27 ml/min, and 35.2 +/- 3.4%. Corresponding values for the centrally directed assay were 51.0 +/- 6.3 min, 1.16 +/- 0.14 ml/min, and 14.4 +/- 1.8%. Clearances of immunoprecipitable 125I-Tyr-SRIF and [125I-Tyr11]SRIF were 6.56 and 1.06 ml/min, respectively, and were not saturable by 1 microM Tyr-SRIF and SRIF, respectively. SRIF (1.26 +/- 0.09 nM) and SRIF-28 (1.34 +/- 0.14 nM) clearances determined by R101 RIA were similar. After SRIF-28 perfusion, high-performance liquid chromatographic analysis of SLI showed 86% to be retained with the SRIF-28 peak and 14% with the SRIF peak, suggesting no major conversion of SRIF-28 to SRIF. Des-(Ala1,Gly2)-N3-Ac-SRIF and dihydrosomatostatin were cleared more rapidly than SRIF. Clearance of SLI by the perfusate without the liver was 12-43% of liver clearance, depending on the peptide examined. These results support the hypothesis that aminopeptidase and endopeptidase activities are involved in SRIF clearance by the intact liver. The activities appear to function independently. The intrachain disulfide bond of SRIF may confer relative stability during its hepatic metabolism.
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PMID:Somatostatin metabolism: differences in clearance of N-terminal and central portions of molecule during perfusion of rat liver. 614 53

Growth hormone (GH)-releasing activity has been detected in extracts of carcinoid and pancreatic islet tumors from three patients with GH-secreting pituitary tumors and acromegaly. Bioactivity was demonstrated in 2 N acetic acid extracts of the tumors using dispersed rat adenohypophyseal cells in primary monolayer culture and a rat anterior pituitary perifusion system. The GH-releasing effect was dose responsive and the greatest activity was present in the pancreatic islet tumor. Small amounts of activity were also found in two other tumors (carcinoid and small cell carcinoma of lung) unassociated with GH hypersecretion. Each of the tumors contained somatostatin-like immunoreactivity but the levels did not correlate with the net biologic expression of the tumor. Sephadex G-75 gel filtration indicated the GH-releasing activity to have an apparent molecular size of slightly greater than 6,000 daltons. The GH-releasing activity was adsorbed onto DEAE-cellulose at neutral pH and low ionic strength, from which it could be eluted by increasing ionic strength. The GH-releasing activity was further purified by high pressure liquid chromatography using an acetonitrile gradient on a cyanopropyl column to yield a preparation that was active at 40 ng protein/ml. Partially purified GH-releasing activity, from which most of the bioactive somatostatin had been removed, increased GH release by pituitary monolayer cultures to five times base line. Enzymatic hydrolysis studies revealed that the GH-releasing activity was resistant to carboxypeptidase, leucine-aminopeptidase, and pyroglutamate-amino-peptidase but was destroyed by trypsin and chymotrypsin, indicating that internal lysine and/or arginine and aromatic amino acid residues are required for biologic activity and that the NH2-terminus and CO9H-terminus are either blocked or not essential. The results provide an explanation for the presence of GH-secreting tumors in some patients with the multiple endocrine neoplasia syndrome, type I, and warrant the addition of GH-releasing activity to the growing list of hormones secreted by tumors of amine precursor uptake and decarboxylation cell types.
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PMID:Partial purification and characterization of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acromegaly. 624 40

We established the cartography of 11 exo- and endopeptidases in the frontal and parietal cortices and in the cerebellum of brains of patients diagnosed with a senile dementia of the Alzheimer's type (SDAT). Comparison with those of four subjects who had died without known neurologic or psychiatric illness indicated that there existed a region-specific alteration of the peptidase contents in the disease. In the frontal area of SDAT brains, postproline dipeptidyl aminopeptidase and aminopeptidase M activities were significantly reduced. In the parietal cortex of SDAT brain, activities of three additional endopeptidases--angiotensin-converting enzyme, proline endopeptidase, and endopeptidase 24.15--were also drastically reduced. In contrast, the cerebellum displayed a set of proteolytic activities that remained unaffected in SDAT brain. The putative influence of the disease on the catabolic fates of neurotensin, neuropeptide Y, and somatostatin(1-14) was investigated. Neurotensin was catabolized at identical rates in the frontal and parietal cortices in nondemented and SDAT brains. In contrast, neuropeptide Y metabolism was slowed down in SDAT brains in the frontal but not in the parietal cortex. Finally, the degradation velocities of somatostatin(1-14) were lowered in both cortical areas of SDAT brains. It is interesting that, by means of specific peptidase inhibitors, we demonstrated that endopeptidase 24.15 participated in somatostatin(1-14) inactivation in the parietal but not in the frontal cortex. It is suggested that the lowering of the rate of somatostatin(1-14) inactivation in the parietal cortex of SDAT brains likely results from the depletion of endopeptidase 24.15 in this brain region.
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PMID:Influence of region-specific alterations of neuropeptidase content on the catabolic fates of neuropeptides in Alzheimer's disease. 790 27

Previously it has been shown that vasopressin (VP) and oxytocin are converted by aminopeptidase activity in brain membranes into fragments with potent CNS activities. This report concerns the properties of this enzyme activity, addressed as VP-converting aminopeptidase (VP-AP) activity, in membranes of the rat brain. The VP-AP activity had a pH optimum at pH 7.0 and had a Km of 17 microM for its action on VP. Amastatin was the most potent aminopeptidase inhibitor. Enzyme activity was inhibited by relatively low concentrations of metal chelators. Treatment of brain membranes by EDTA resulted in loss of enzyme activity that was completely reversed by 10 microM Zn2+, indicating that VP-AP activity is a metallopeptidase. Several VP analogues and fragments, in particular VP(1-8), inhibited the action of enzyme activity on VP. Among peptides unrelated to VP, angiotension I, somatostatin, and porcine ACTH(1-39) markedly inhibited enzyme activity. Solubilization of VP-AP activity from brain membranes and gel filtration on Sephadex G200 showed two peaks of activity, one eluting with an apparent mass of about 140 kDa, the other in the void volume. Gel filtration fractions were able to convert [3H][Phe3]VP in a step-wise fashion. The VP-AP-like activity was found in many tissues outside the brain. Highest activity was present in lung, kidney, parts of the gastrointestinal tract, ovary, and uterus. The results indicate that VP-AP activity is a widely distributed enzyme with probably multiple functions, one of which involves the metabolism of vasopressin in the brain.
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PMID:Properties of aminopeptidase activity involved in the conversion of vasopressin by rat brain membranes. 799 91

A metalloendopeptidase that selectively cleaves doublets of basic amino acids on the amino-terminal side of arginine residues was purified to homogeneity from rat testes and analyzed further. Two catalytically active forms with apparent relative molecular masses of 110,000 and 140,000 Da, respectively, were present in the purified preparation of the enzyme. Antibodies raised against the purified testis endopeptidase revealed by immunoblot both the 110- and 140-kDa forms in both rat testis and brain cortex extracts. The isolated enzyme was inhibited by metal chelators and divalent cations. Its activity, lost after preincubation with EDTA, was restored by low concentrations of Zn2+ and Mn2+, thus demonstrating the metallopeptidase nature of the enzyme. This endopeptidase also exhibited a high sensitivity to amastatin (100% inhibition at 20 microM), an aminopeptidase inhibitor. A substrate specificity study using physiologically important or synthetic peptides containing a processing dibasic site indicated that cleavage occurred selectively at the amino-terminal side of an arginine residue, independent of the nature of the basic doublet. The enzyme produced such a cleavage at the Arg-Lys doublet of somatostatin 28 (Km = 43 microM), at the Arg-Arg doublet of dynorphin A (Km = 6.45 microM) and atrial natriuretic factor (Km = 6.25 microM), and at the Lys-Arg doublet of preproneurotensin-(154-170) (Km = 17.3 microM). Moreover, cleavage efficiency was found to be higher for the larger substrates. The distinctive properties of this endopeptidase imply that this protein is a member of a novel class of proteolytic enzymes that may be involved in the endoproteolytic maturation of hormonal precursors.
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PMID:Isolation and characterization of a dibasic selective metalloendopeptidase from rat testes that cleaves at the amino terminus of arginine residues. 829 57


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