Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nine cases of endocrine carcinoma, intermediate-cell type of the uterine cervix, were found in a study of 404 cases listed in the files of the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston as adenocarcinoma of the cervix. Based on light microscopic patterns, these cases were divided into pure endocrine carcinoma (six cases), and endocrine carcinoma mixed with adenocarcinoma (three cases). All tumors were 3 cm or larger in at least one dimension. On light microscopic examination, the predominant pattern was trabecular; however, insular, glandular, and spindle patterns were also identified. Argyrophilic granules were demonstrated in all cases by Grimelius stain, and Fontana-Masson (argentaffin) stain was negative. Electron microscopic examination of three cases showed membrane-bound, dense-core granules of the neurosecretory type. Although no endocrine symptoms were found, immunoperoxidase studies demonstrated 5-hydroxytryptamine in seven cases, substance P in three, vasointestinal polypeptide in two, pancreatic polypeptide in one, and somatostatin in one. Clinical behavior of these tumors was extremely aggressive. Although five cases were Stage IB at presentation, two Stage IIB, one Stage IIIB, and one Stage IV, 87.5% of these patients died of their neoplasms within 3 years. This study emphasizes the importance of correctly diagnosing endocrine carcinoma, intermediate-cell type in the uterine cervix, because of the poor prognosis of this tumor when compared with adenocarcinoma of the cervix.
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PMID:Endocrine carcinoma intermediate cell type of the uterine cervix. 638 96

Secretory vesicles isolated from the neural and intermediate lobes of the bovine pituitary contained a membrane-bound aminopeptidase activity which cleaved arginine from beta-LPH60-65 (Arg-Tyr-Gly-Gly-Phe-Met) and Arg-MCA. Neither methionine enkephalin (Tyr-Gly-Gly-Phe-Met) nor Substance P, which has an N-terminal arginine followed by a proline, could serve as substrates for this aminopeptidase activity; nor could cathepsin B-like or chymotrypsin-like enzyme activities be detected in the vesicle preparations. Maximal enzyme activity was at pH 6.0, and the activity was inhibited by EDTA, stimulated by Co2+ and Zn2+, but was unaffected by leupeptin, pepstatin A, phenylmethylsulfonyl fluoride and p-chloromercuribenzenesulfonate, suggesting that the enzyme is a metalloaminopeptidase. The presence of this aminopeptidase activity in secretory vesicles suggests that it may be involved in peptide prohormone processing.
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PMID:An aminopeptidase activity in bovine pituitary secretory vesicles that cleaves the N-terminal arginine from beta-lipotropin60-65. 643 44

A membrane-bound enzyme which degrades substance P (an undecapeptide) has been purified from human brain. The properties of this enzyme suggest that it may be involved in the physiological inactivation of the peptide by neural tissues. Enzyme activity was extracted from a membrane fraction of human diencephalon with a non-ionic detergent, Brij 35, and activity was monitored by measuring the disappearance of added substance P using radioimmunoassay, bioassay or radiochemical assay. The enzyme was purified about 1000-fold by chromatography on DEAE-cellulose, hydroxyapatite and Sephadex gel filtration columns. To identify the cleavage sites in substance P, the peptide was incubated with the purified enzyme and the breakdown products were separated by reverse-phase high-performance liquid chromatography and identified by amino acid analysis. The results suggested that the enzyme preparation was functionally homogeneous and it cleaved substance P between Gln6-Phe7, Phe7-Phe8 and Phe8-Gly9, with no exopeptidase action. The enzyme had a pH optimum in the range 7--9 and was strongly inhibited by metal-chelating agents, but not affected by most other peptidase inhibitors; it can thus be classified as a neutral metallo-endopeptidase. The enzyme was thermolabile and had a molecular weight of 40 000--50 000 as estimated by gel filtration, density-gradient ultracentrifugation and sodium dodecylsulphate gel electrophoresis. The highly purified substance-P-degrading enzyme could be distinguished from previously described peptidases for which substance P is a substrate. An important feature was that substance P was the preferred substrate among various other neuropeptides tested.
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PMID:Purification and characterisation of a membrane-bound substance-P-degrading enzyme from human brain. 701 9

Interleukin-1 (IL-1) induction of substance P (SP) in cultured sympathetic ganglia requires a soluble intermediate molecule that is present in IL-1 conditioned medium (IL-1CM). One of the required intermediates is leukemia inhibitory factor (LIF; Shadiack et al., J Neurosci 13:2601-2609, 1993). In the present study we have examined the possibility that ciliary neurotrophic factor (CNTF) is another intermediate involved in the IL-1 induction of sympathetic SP. CNTF mimics the action of IL-1CM by raising both SP and choline acetyltransferase activity--actions that are blocked by a specific neutralizing antiserum for CNTF. However, IL-1CM and CNTF differ in their response to depolarizing agents: while KCl (40 mM) blocks the action of IL-1CM (and LIF), it enhances the action of CNTF. Furthermore, neither CNTF bioactivity nor CNTF protein is detected in IL-1CM. Neutralizing antiserum to CNTF fails to block the action of either IL-1 or IL-1CM, suggesting that neither a soluble nor a membrane-bound form of the molecule is active in direct response to IL-1 action. While Northern blots confirm the presence of both CNTF and CNTF receptor mRNA in neonatal ganglia, neither culturing nor IL-1 treatment alters these mRNA levels. These data taken together suggest that while CNTF is present and possibly active in sympathetic ganglia, it is not a mediator of the IL-1 induction of SP.
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PMID:The interleukin-1-induced increase of substance P in sympathetic ganglia is not mediated by ciliary neurotrophic factor. 752 14

Aminopeptidase N (EC 3.4.11.2) is an important enzyme that is involved in the degradation of regulatory peptides including enkephalins. We report here that purified and native membrane-bound aminopeptidase N will sequentially and completely hydrolyze both Leu-enkephalin and Met-enkephalin from the amino terminus. Both purified pig aminopeptidase N and the enzyme on live HL60 cells displayed similar Km values for enkephalin. The naturally occurring neuropeptides substance P and bradykinin, and the morphine agonist, morphiceptin, were not hydrolyzed by aminopeptidase N and each inhibited the enzymatic activity. Each of these peptides contains a proline at the second residue. The Ki values for substance P (0.44 microM), bradykinin (9.4 microM), and morphiceptin (169 microM) were obtained with the enzyme on live HL60 cells. The values for the purified enzyme from pig were similar. The potent inhibition of aminopeptidase N by substance P and bradykinin suggests that these peptides may be natural inhibitors of the enzyme.
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PMID:Substance P and bradykinin are natural inhibitors of CD13/aminopeptidase N. 753 53

Neutral endopeptidase 24.11, a membrane-bound metallopeptidase, cleaves, and degrades vasoactive peptides such as atrial natriuretic peptide, endothelin, angiotensin I, substance P, and bradykinin. Therefore, the presence of this metallopeptidase may contribute to the regulation of vascular tone and local inflammatory responses in the vascular endothelium and elsewhere. We determined neutral endopeptidase in cultured human endothelial cells from different vascular beds and studied its regulation by protein kinase C. Neutral endopeptidase was detected in all cultured endothelial cell types. Lowest concentrations were measured in human endothelial cells from umbilical veins (360 +/- 14 pg/mg protein), followed by pulmonary and coronary arteries; higher concentrations were found in endothelial cells from the cardiac microcirculation (1099 +/- 73 pg/mg protein). Neutral endopeptidase content increased during cell growth but was not affected by endothelial cell growth factor or modifications of the growth medium. Stimulation of protein kinase C with 1-oleoyl-2-acetyl-rac-glycerol (0.1 to 1 mumol/L) and phorbol 12-myristate 13-acetate (0.01 to 0.1 mumol/L) induced a time- and concentration-dependent increase of endothelial cells that was inhibited by cycloheximide (5 mumol/L), an inhibitor of protein synthesis. Incubation with phospholipase C (1 mumol/L) and thrombin (10 IU/mL) induced upregulation of neutral endopeptidase, resulting in 158 +/- 26% and 150 +/- 22% increases, respectively, compared with controls. The thrombin effect was inhibited by calphostin C (1 mumol/L), an inhibitor of protein kinase C. Endothelial neutral endopeptidase is constitutively expressed in endothelial cells from different origins and is inducible by thrombin via activation of the protein kinase C pathway.
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PMID:Regulation and differential expression of neutral endopeptidase 24.11 in human endothelial cells. 763 30

The cases of three patients with primary carcinoid tumor of the testis were reported. The patients were 41, 44, and 83 years of age. At initial examination, all three had testicular masses with or without associated pain, and none had the carcinoid syndrome. The tumors measured 4.3 cm, 3.0 cm, and 6.5 cm in dimension. All three tumors manifested classic histologic features of carcinoid tumors. The neoplastic cells exhibited argyrophilia, and all were immunoreactive to chromogranin, serotonin, neuron-specific enolase, and cytokeratin. Two tumors had positive test results for gastrin and one had positive test results for substance P and vasoactive intestinal polypeptide. No tumors reacted with somatostatin, insulin, pancreatic polypeptide, or placental alkaline phosphatase. Intracytoplasmic, membrane-bound, round-to-elliptical pleomorphic granules were identified by ultrastructural analysis in all cases. DNA flow cytometric analysis revealed a low degree (near-diploid) DNA aneuploidy in all cases, with a DNA index of 1.15 in two tumors and 1.3 in the third tumor. The three patients are alive and well 11 years, 7 years, and 6 months, respectively, after diagnosis. A total of 57 cases of this entity, including the 3 reported here, have been reported. Of these, 43 were pure carcinoid, and 14 were associated with teratoma; 6 (11.6%) patients developed metastases. Tumor size and the presence of carcinoid syndrome have been found to correlate with metastatic potential. Neither tumor necrosis nor local tumor invasion (into vessels, tunica albuginea, etc.) correlated with adverse prognosis. Carcinoid tumor of the testis is a rare indolent neoplasm with potential for distant metastases.
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PMID:Primary carcinoid tumor of testis. Immunohistochemical, ultrastructural, and DNA flow cytometric study of three cases with a review of the literature. 768 60

Senktide is a highly specific and potent analog of neurokinin B, the natural ligand of the tachykinin receptor NK-3. The membrane-bound conformation of senktide, interacting with negatively charged membrane vesicles composed of perdeuterated phosphatidylcholine and phosphatidylglycerol (70:30), has been investigated using two-dimensional transferred nuclear Overhauser effect spectroscopy (TRNOESY). The occurrence of an N-methylated phenylalanine in the peptide's sequence induces a cis-trans-isomerisation of the corresponding peptide bond which is slow on the chemical-shift scale. NMR data indicate a much stronger membrane affinity of the trans isomer, allowing the determination of a highly resolved membrane-bound conformation using distance geometry and energy minimization. The membrane-bound backbone conformation of several residues is found to be close to a left-handed helix, certainly due to the presence of nonnatural residues (succinylated N-terminal, N-methyl-phenylalanine) as well as a glycine. The results are discussed in the context of a possible biological relevance of the membrane-bound conformation, in terms of the affinity and specificity of this neuropeptide.
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PMID:1H nuclear magnetic resonance determination of the membrane-bound conformation of senktide, a highly selective neurokinin B agonist. 769 Dec 90

A neutral endoprotease was isolated from porcine antral mucosa and purified to homogeneity as examined by SDS-polyacrylamide gel electrophoresis (PAGE). Throughout the purification, t-butyloxycarbonyl-Arg-Val-Arg-Arg-4- methylcoumaryl-7-amide (MCA) was used as a substrate, which was found to be hydrolyzed specifically by the enzyme at the Arg-Arg bond. Unexpectedly, however, the enzyme was also found to hydrolyze vasoactive intestinal polypeptide (VIP) fairly specifically and more efficiently when various neuropeptides and related peptides were examined as substrates. It could degrade VIP by cleaving three peptide bonds not containing an arginine residue(s) with Km = 7.7 x 10(-6) M and kcat/Km = 7.4 x 10(6) M-1 s-1 (at pH 7.6 in the presence of 0.1% Lubrol PX), whereas only secretin, substance P, and a few others were hydrolyzed at much slower rates among the various peptides examined. Both activities toward the MCA substrate and VIP behaved in parallel throughout the purification procedures and showed essentially the same pH optimum and susceptibility toward various inhibitors and detergents. Therefore, both activities are thought to be due to the same enzyme. This endoprotease required 0.001% or a higher concentration of a detergent such as Lubrol PX or Triton X-100 for its maximal activity. Its optimum pH was about 7.5 and the molecular weight was estimated to be approximately 37,000 by SDS-PAGE. This enzyme was strongly inhibited by serine protease inhibitors such as diisopropyl-fluorophosphate and phenylmethanesulfonyl fluoride. It was also inhibited by p-chloromercuribenzoic acid, but not by some other cysteine protease inhibitors. Therefore, the enzyme appears to be most likely a kind of serine protease although its possibility as a cysteine protease cannot be completely excluded. Analysis of its cleavage specificity toward various oligopeptides indicated the possibility that the protease might recognize a specific amino acid sequence(s) and/or conformation in the vicinity of the cleavage site of the target peptide. Various characteristics of the endoprotease suggest that it is a novel membrane-bound neuropeptide-degrading endoprotease fairly specific for VIP.
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PMID:Purification and characterization of a vasoactive intestinal polypeptide-degrading endoprotease from porcine antral mucosal membranes. 771 70

The action of neuropeptides at the synapse is terminated through enzymatic degradation by membrane-bound proteases. We defined and purified membrane-bound proteases functioning at the initial stage of degradation of four neuropeptides. 1. Substance P-degrading endopeptidases isolated from the rat brain and pig striatum showed similar properties to those of endopeptidase-24.16 (neurolysin) except for cleavage sites of substance P. 2. LHRH fragment (1-5)-generating endopeptidases isolated from the neuroblastoma cells and rat brain showed similar properties to those of endopeptidase-24.15 (thimet oligopeptidase). 3. One of two dynorphin-degrading cysteine proteases isolated from neuroblastoma cells showed strict specificity toward the Arg-Arg residues. 4. Endopeptidase-24.11 (neprilysin) isolated from the rat brain was identified as a somatostatin-degrading enzyme.
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PMID:[Membrane-bound proteases involved in neuropeptide degradation in the brain]. 836 28


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