Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several reports have described decreased immunoreactive somatostatin levels in specific regions of post-mortem brain tissue from patients diagnosed with senile dementia of the Alzheimer type (SDAT). In an attempt to determine if the metabolism of somatostatin is also altered as a result of SDAT, we examined the regional metabolic half-life of somatostatin-28 (SS-28) and somatostatin-14 (SS-14). The activity of the following peptidases was also determined: neutral endopeptidase E.C. 3.4.24.11; metalloendopeptidase E.C. 3.4.24.15; carboxypeptidase E (E.C. 3.4.17.10); and trypsin-like serine protease. The metabolic half-life of SS-28 was significantly reduced in post-mortem Brodmann Area 22 of SDAT tissue. This decrease in SS-28 metabolic half-life was correlated with a significant increase in trypsin-like serine protease activity in the same SDAT brain region. The formation rate of SS-14 from SS-28 incubated with Brodmann Area 22 homogenates was also increased in SDAT tissues as compared to controls. A regional variation in neutral endopeptidase E.C. 3.4.24.11 was also noted in both controls and SDAT samples. Although postmortem intervals of samples varied significantly, no effect was seen on any biochemical parameter measured. Results from this study provide evidence that a correlation can be made between changes in metabolic half-life somatostatin and alterations in neuropeptidase activities due to SDAT. As these data show alterations in both proteolytic metabolism and peptidase activities, many other biologically active peptide substrates could also be affected in SDAT.
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PMID:Metabolic half-life of somatostatin and peptidase activities are altered in Alzheimer's disease. 134 49

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

Plasma membrane vesicles were prepared from the basolateral face of pig small intestinal epithelial cells and were enriched in the activity of Na+-K+-ATPase (9-fold relative to the cell homogenate) and ranged in size from 0.15 to 0.40 micron diam. Incubation of somatostatin-14 and [125I-Tyr11]-somatostatin-14 with the vesicles at 37 degrees C resulted in rapid proteolytic degradation of the peptides. Metabolites were isolated by reverse-phase high-performance liquid chromatography and identified by amino acid composition. Cleavages between Ala1-Gly2, Phe6-Phe7, Phe7-Trp8, and Thr10-Phe11 were observed, indicative of aminopeptidase and endopeptidase action. Degradation was inhibited by 1,10-phenanthroline and by bacitracin, and in the presence of these inhibitors and at 21 degrees C binding of [125I-Tyr11]somatostatin-14 to the vesicles was observed. Binding was inhibited in a concentration-dependent manner by somatostatin-14 (half-maximal inhibition at 2.0 +/- 0.1 nM) and by somatostatin-28 (0.8 +/- 0.1 nM) but not by structurally unrelated peptides. The rate of degradation of [125I-Leu8, D-Trp22, Tyr25]somatostatin-28 by basolateral membrane was less than 20 fold that of [125I-Tyr11]somatostatin-14 and a two- to three-fold enhanced binding to the vesicles was observed. Analysis of the inhibition of binding of this analogue by somatostatin-28 indicates the presence of single class of binding site with Kd = 1.3 +/- 0.3 nM. Rapid degradation but no specific binding of somatostatin-14 by brush-border membranes was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific binding and degradation of somatostatin by membrane vesicles from pig gut. 287 63

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

Anglerfish (Lophius piscatorius) Brockmann organs contain a form of somatostatin-14, identical to the hypothalamic tetradecapeptide, and two distinct forms of somatostatin-28, which can be separated by reversed-phase high-pressure liquid chromatography (HPLC). Analysis of the NH2-terminal amino acid sequence and comparison of the ability to incorporate 125I indicate that one of these forms corresponds to an octacosapeptide including in its sequence the (Tyr-7, Gly-10) derivative of somatostatin-14 (somatostatin II). Exposure of this somatostatin-28 species to an endopeptidase activity from the rat brain cortex generates a peptide immunologically related to somatostatin and undistinguishable from synthetic (Tyr-7, Gly-10) somatostatin-14 II by HPLC. This somatostatin-28 II exhibits a potent inhibitory effect on growth hormone release by rat anterior pituitary cells, comparable to the other somatostatin-28 form. Since (Tyr-7, Gly-10) somatostatin-14 II cannot be detected in anglerfish pancreatic islets, these results indicate that somatostatin-28 II represents the terminal active product of prosomatostatin II processing, whose structure was predicted from the cDNA nucleotide sequence corresponding to the second mRNA cloned from anglerfish Brockmann organs [Hobart, P., Crawford, R., Shen, L. P., Pictet, R. & Rutter, W. J. (1980) Nature (London) 288, 137-141].
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PMID:Characterization of a somatostatin-28 containing the (Tyr-7, Gly-10) derivative of somatostatin-14: a terminal active product of prosomatostatin II processing in anglerfish pancreatic islets. 615 Apr 81

The membrane metalloenzyme endopeptidase-24.11 has been localized by immunocytochemistry in the porcine hippocampus in the stratum oriens and stratum radiatum. Endopeptidase-24.11 was found to be approximately 10-fold more abundant in a striatal than a hippocampal membrane preparation. Both somatostatin-28 and somatostatin-14 were metabolized by endopeptidase-24.11, but the kinetics of hydrolysis markedly favoured the smaller form of the neuropeptide. After phase separation with Triton X-114 of striatal and hippocampal membrane preparations, and by using selective inhibitors, the major (> 80%) somatostatin-metabolizing activity was found to partition into the detergent-rich phase and was attributable predominantly to endopeptidase-24.11. The residual activity observed in the presence of the selective endopeptidase-24.11 inhibitor phosphoramidon was blocked by Pro-Ile or N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate, inhibitors of endopeptidase-24.16 and endopeptidase-24.15, respectively. However, Pro-Ile, at comparable concentrations, was shown to inhibit endopeptidase-24.11, challenging the validity of its use as a selective inhibitor of endopeptidase-24.16. The immunocytochemical and Triton X-114 phase-separation data implicate endopeptidase-24.11, rather than endopeptidase-24.16 or endopeptidase-24.15, as the major physiological somatostatin-degrading neuropeptidase in the striatum and hippocampus.
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PMID:Endopeptidase-24.11 is the integral membrane peptidase initiating degradation of somatostatin in the hippocampus. 789 Nov 11

A new metallo-endopeptidase which hydrolyzes atrium natriuretic factor (ANF) has been isolated from human neuroblastoma NB-OK-1 cells. In the present study we show that this metallo-endopeptidase is also present in several other human neuroblastoma cell lines, which include CHP 100, SH-SY5Y, SK-N-BE(2), BE(2)-C and BE(2)M-17. Additionally, we show that this endopeptidase activity is reduced to about 20% of the control during retinoic acid (RA)-induced neuronal differentiation in the RA-sensitive SK-N-BE(2) cells, but not in the RA-resistant BE(2)-M17 cells. This suggests that the inhibition is related to neuronal differentiation and not to a direct effect of 5 microM RA on the enzyme activity. This new enzyme is clearly distinct from neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-converting enzyme (ACE,EC 3.4.15.1), since specific inhibitors for these endopeptidases (10 microM phosphoramidon and 1 mM captopril, respectively) had no effect on their activity. However, this enzyme was inhibited 100% by 10 mM o-phenanthroline showing an inhibitory spectrum similar to that of another novel metallo-endopeptidase recently isolated in our laboratory from Xenopus laevis skin secretion. Although the physiological function of this new enzyme in human neuroblastoma cells is not known at the present time, we suggest that it may participate in inactivation of neuropeptides such as atrium natriuretic factor (ANF), substance P, somatostatin-14 and bradykinin in vivo.
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PMID:Human neuroblastoma cells express a novel metallo-endopeptidase activity able to inactivate atrial natriuretic factor: inhibition during retinoic acid-induced differentiation. 813 18

The objectives of this investigation were to characterize neuropeptide-degrading enzymes on the surface of gastric muscle cells and to determine their physiological function. Neutral endopeptidase (NEP, EC 3.4.24.11) activity was measured using the fluorogenic substrate glutaryl-Ala-Ala-Phe-4-methoxy-2-naphthylamine. The NEP inhibitors phosphoramidon and DL-thiorphan (1 microM) inhibited degradation of the substrate by gastric muscle membranes by 100% and by freshly dispersed gastric muscle cells by 55-60%. The phosphoramidon or DL-thiorphan-inhibitable activity, attributed to NEP, of membranes was 112 +/- 4.0 pmol h-1 (micrograms protein)-1 and of cells was 4.2 +/- 0.8 nmol h-1 (10(6) cells)-1. This activity was associated with membranes prepared from cells and was not detected in the cytoplasm or in the cell incubation solution. Gastric muscle membranes were fractionated by electrophoresis and analysed by Western blotting using two NEP antisera. Both antisera recognized a protein in membranes with an electrophoretic mobility identical to that of recombinant human NEP and an apparent molecular mass of approximately 95 kDa. Neuropeptides were degraded by membranes with specific activities in the order of [Leu5]enkephalin > [Met5]enkephalin > gastrin-releasing peptide-10 (GRP-10) > [D-Ala2][Leu5]enkephalin > somatostatin-14. Phosphoramidon and DL-thiorphan similarly inhibited the degradation of GRP-10 (mean of 35% inhibition), somatostatin-14 (57%) and the aminopeptidase-resistant analogue, [D-Ala2][Leu5]enkephalin (75%). When aminopeptidases were inhibited with amastatin (10 microM) phosphoramidon inhibited degradation of [Leu5]enkephalin (54%) and [Met5]enkephalin (100%). Phosphoramidon increased the potency of the contractile effects of neuropeptides on muscle cells by > 280-fold for somatostatin-14, 17-fold for GRP-10, 18-fold for [Met5]enkephalin and 14-fold for [Leu5]enkephalin. The results show that an NEP-like enzyme on the surface of gastric muscle cells degrades and inactivates enkephalins, GRP-10 and somatostatin-14 and acts in a manner analogous to that of acetylcholinesterase in the neuromuscular junction of skeletal muscle.
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PMID:Neutral endopeptidase (EC 3.4.24.11) modulates the contractile effects of neuropeptides on muscle cells from the guinea-pig stomach. 844 12

Peptide hormone inactivating endopeptidase (PHIE) is a metalloendopeptidase which was isolated from the skin granular gland secretions of Xenopus laevis [Carvalho, K. M., Joudiou, C., Boussetta, H., Leseney, A. M., & Cohen, P. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 84-88]. This peptidase exhibits a thermolysin-like character and hydrolyzes bonds on the amino terminus of hydrophobic amino acids, performing cleavage of Xaa-Phe, Xaa-Leu, Xaa-Ile, Xaa-Tyr, and Xaa-Trp doublets. When the enzyme recognized a doublet of hydrophobic amino acids such as Phe6-Phe7 of somatostatin-14, Phe7-Phe8 of substance P, Phe4-Leu5 of [Leu5,Arg6]enkephalin, and Tyr4-Ile5 of angiotensin II, cleavage occurred preferentially between these residues. The use of selectively modified carboxy-terminal octapeptide fragments of atrial natriuretic factor (ANF) indicated that the enzyme tolerates as substrates only peptides bearing a P'1 bulky hydrophobic amino acid residue. Although a P'1 hydrophobic residue was a necessary condition, it was found in a number of peptides that all potential cleavage sites were not recognized by the enzyme. These data suggested that this metalloendoprotease requires for its thermolysin-like activity a preferred conformation of the peptide chain. Kinetic results obtained using a series of related substrates derived from biologically active peptides of the atrial natriuretic factor, tachykinin, and enkephalin families indicated the presence of an extended binding site accommodating at least six amino acid residues, in contrast to thermolysin (EC 3.4.24.4) and neutral endopeptidase (NEP; EC 3.4.24.11), which hydrolyze shorter homologous peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the thermolysin-like cleavage of biologically active peptides by Xenopus laevis peptide hormone inactivating enzyme. 850 36


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