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)

Aminopeptidase M (EC 3.4.11.2), an enzyme present on the cell surface of vascular endothelium and/or smooth muscle, rapidly hydrolyzes leucyl- and arginyl-2-naphthylamides and a number of vasoactive peptides at physiologic pH. Utilizing both thin-layer chromatography and high pressure liquid chromatography, it was found that vascular aminopeptidase M converted kallidin to bradykinin and inactivated des(Asp1)angiotensin I, angiotensin III, hepta(5-11)substance P and hexa(6-11)substance P. Aminopeptidase M did not, however, hydrolyze bradykinin, angiotensin I, angiotensin II, saralasin, vasopressin, oxytocin or any form of substance P containing a component of the Arg-Pro-Lys-Pro sequence. Both the naphthylamidase and peptidase activities were inhibited similarly by known amino-peptidase M inhibitors including o-phenanthroline, amastatin, bestatin and puromycin. However, inhibitors of angiotensin I converting enzyme (captopril), carboxypeptidase N (MERGETPA), neutral endopeptidase (phosphoramidon), post proline cleaving enzyme and dipeptidyl(amino)peptidase IV (diisopropylphosphofluoridate, DFP) were without effect. These results demonstrate that vascular, cell surface aminopeptidase M can selectively metabolize vasoactive peptides and may play a role in modulating their levels in the circulation and/or within the vessel wall.
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PMID:Vascular, plasma membrane aminopeptidase M. Metabolism of vasoactive peptides. 240 81

The catabolism of two gastric neuropeptides, the C-terminal decapeptide of gastrin releasing peptide-27 (GRP10) and substance P (SP), by membrane-bound peptidases of the porcine gastric corpus and by porcine endopeptidase-24.11 ("enkephalinase") has been investigated. GRP10 was catabolized by gastric muscle peptidases (specific activity 1.8 nmol min-1 mg-1 protein) by hydrolysis of the His8-Leu9 bond and catabolism was inhibited by phosphoramidon (I50 approx. 10(-8) M), a specific inhibitor of endopeptidase-24.11. The same bond in GRP10 was cleaved by purified endopeptidase-24.11, and hydrolysis was equally sensitive to inhibition by phosphoramidon. SP was catabolized by gastric muscle peptidases (specific activity 1.7 nmol min-1 mg-1 protein) by hydrolysis of the Gln6-Phe7, Phe7-Phe8 and Gly9-Leu10 bonds, which is identical to the cleavage of SP by purified endopeptidase-24.11. The C-terminal cleavage of GRP10 and SP would inactivate the peptides. It is concluded that a membrane-bound peptidase in the stomach wall catabolizes and inactivates GRP10 and SP and that, in its specificity and sensitivity to phosphoramidon, this peptidase resembles endopeptidase-24.11.
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PMID:Catabolism of gastrin releasing peptide and substance P by gastric membrane-bound peptidases. 241 13

Metabolites of substance P, produced by incubation with isolated epithelial cells and with purified brush border and basolateral membrane from pig small intestine, were isolated by high performance liquid chromatography and identified by amino acid analysis. Rapid cleavages between Gln6-Phe7, Phe7-Phe8 and Gly9-Leu10 and oxidation of the methionine residue at position 11 were observed with cells and with both membrane fractions. Formation of substance P3-11' indicative of the action of dipeptidylaminopeptidase IV (EC 3.4.14.5), was observed only at high substrate concentration. Proteolytic degradation was inhibited by phosphoramidon and by EDTA but was insensitive to chloride ion concentration and to captopril. These observations suggest that inactivation of substance P in the epithelial layer of the gut is mediated through endopeptidase-24.11 (EC 3.4.24.11) in the cell-surface membrane and that degradation by angiotensin-converting enzyme (EC 3.4.15.1), although present in high concentration in the mucosa, is unimportant.
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PMID:Proteolytic inactivation of substance P in the epithelial layer of the intestine. 241 32

Calcitonin gene-related peptide (CGRP) was found to potently inhibit a substance P endopeptidase isolated from human CSF. CGRP potentiated substance P irritant actions; a possible mechanism is interaction for a common metabolic step. Somatostatin is another peptide capable of competing with substance P endopeptidase.
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PMID:Calcitonin gene-related peptide is a potent inhibitor of substance P degradation. 241 71

Angiotensin I converting enzyme (ACE) and neutral endopeptidase ("enkephalinase"; NEP), were purified to homogeneity from human renal membranes. NEP hydrolyzed substance P (SP) at Gln6-Phe7, Phe7-Phe8, and Gly9-Leu10 and neurotensin (NT) at Pro10-Tyr11 and Tyr11-Ile12. ACE cleaved SP at Phe8-Gly9 and Gly9-Leu10 to release C-terminal tri- and dipeptide (ratio = 4:1). The hydrolysis was dependent on chloride ion and inhibited by captopril. Modification of arginine residues in ACE with cylcohexanedione or butanedione inhibited hydrolysis of SP, bradykinin and Bz-Gly-Phe-Arg (80-93%) indicating an active site arginine is required for hydrolysis of SP. ACE cleaved NT at Tyr11-Ile12 to release Ile12-Leu13. These studies indicate that ACE and NEP, two enzymes which are widely distributed in the body, may be involved in the metabolism of SP and NT.
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PMID:Characterization of the metabolism of substance P and neurotensin by human angiotensin I converting enzyme and "enkephalinase". 241 54

Hydrolysis of substance P and nine kinds of substance P analogs by angiotensin-converting enzyme highly purified from rat lung was examined by using amino-group fluorometry and high-performance liquid chromatography. The enzyme hydrolyzed substance P and several analogs, notwithstanding that they did not contain free C-terminal residues. The analyses of cleavage products separated by high-performance liquid chromatography indicated that the enzyme hydrolyzed substance P and its analogs mainly at the bond between Phe8-Gly9 and also at another bond, possibly between Gly9-Leu10, to a lesser extent by an endopeptidase action, followed by successive release of dipeptides by a dipeptidyl carboxypeptidase action. The analogs that had D-amino acid residues substituted at the presumed cleavage sites were scarcely hydrolyzed. It was further found that (Pyr6)-fragment (6-11) was hydrolyzed by the enzyme more efficiently than the other fragment-type analogs and was cleaved at a single bond by the endopeptidase activity of the enzyme. Therefore, this fragment was used as a substrate in order to characterized the endopeptidase activity of the enzyme by employing fluorometry. The activity was dependent on chloride ion, and was inhibited by captopril, MK-421, and EDTA. Thus, the endopeptidase activity of the enzyme showed properties similar to those of the dipeptidyl carboxypeptidase activity of the enzyme.
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PMID:Hydrolysis of substance P and its analogs by angiotensin-converting enzyme from rat lung. Characterization of endopeptidase activity of the enzyme. 241 12

The purpose of this investigation was to examine the pathway of substance P (SP) and neurotensin (NT) catabolism in the gastric wall of the rat and identify some of the enzymes involved. Under anaesthesia an infusion catheter and a bundle of dialysis fibres were implanted into the stomach wall of the rat. Experiments commenced on conscious rats 2 days after surgery. In control experiments [3H]-SP(Pro-2,4) or [3H]-NT(Tyr-3,11) were injected into gastric tissues through the catheter and catabolites were collected in the dialysis fibres and separated by high pressure liquid chromatography. In other studies captopril, MK422 (inhibitors of angiotensin converting enzyme) or phosphoramidon (an inhibitor of endopeptidase-24.11, 'enkephalinase') were injected into gastric tissues before the peptide label. SP1-11 was degraded to mainly SP1-2, SP3-4 with some SP1-6, SP1-7 and SP1-8. Catabolism was partially but significantly (5% level) inhibited by MK422 and captopril, but not by phosphoramidon. NT1-13 was degraded to NT1-8, NT9-13, NT1-11 and NT1-12. NT catabolism was partially but significantly (5% level) inhibited by MK422. It is concluded that an enzyme resembling angiotensin converting enzyme is involved in the initial stages of SP and NT catabolism in the rat stomach. The involvement of other peptidases cannot be excluded because inhibition of breakdown was not complete.
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PMID:Catabolism of substance P and neurotensin in the rat stomach wall is susceptible to inhibitors of angiotensin converting enzyme. 242 51

Membrane vesicles, showing a 21 +/- 2-fold enrichment in the activity of 5'-nucleotidase and a 11 +/- 4-fold enrichment in the activity of angiotensin-converting enzyme relative to homogenate, were prepared from the myenteric plexus-containing longitudinal muscle layer of guinea pig ileum. Incubation of the vesicles with substance P and neurokinin A led to degradation of the peptides, and metabolites were isolated by reverse-phase HPLC and identified by amino acid composition. Cleavages of substance P between Glu6-Phe7, Phe7-Phe8, and Gly9-Leu10 and of neurokinin A between Gly8-Leu9 were observed and could be inhibited in a dose-dependent manner by phosphoramidon, an inhibitor of neutral endopeptidase 24.11. Formation of these metabolites was not completely inhibited by this agent, indicating that a phosphoramidon-insensitive form of endopeptidase 24.11 was present in the gut. Substance P was resistant to degradation by aminopeptidases, but neurokinin A was a substrate for bestatin-sensitive aminopeptidase(s), so that the neurokinin A (3-10) fragment represented the predominant metabolite in the chromatograms. The rate of formation of all the metabolites was not inhibited by enalapril and not enhanced by an increased Cl- concentration, indicating that angiotensin-converting enzyme was unimportant in the degradation process. Degradation of neurokinin A by the vesicles (Km 30 microM; Vmax 7.2 +/- 0.8 nmol min-1 mg of protein-1) was more rapid than degradation of substance P (Km 25 microM; Vmax 4.4 +/- 0.4 nmol min-1 mg of protein-1).
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PMID:Proteolytic inactivation of substance P and neurokinin A in the longitudinal muscle layer of guinea pig small intestine. 242 10

To study the roles of substance P (SP) and endogenous peptidases in regulating mucus secretion from ferret trachea, we measured the SP-induced release of 35SO4-labeled macromolecules after incubating segments of trachea in Ussing chambers in the presence and absence of selected inhibitors of proteolytic enzymes. Our strategy was based on the idea that if endogenous peptidases degrade SP, then inhibitors of these enzymes should potentiate SP-induced secretion. We found that tracheas of ferrets contained SP-like immunoreactivity, and that SP stimulated the release of bound 35SO4 with rapid onset and offset. Eighty-five percent of the total macromolecular radioactivity released was contained in fractions of molecular weights greater than 10(6). The response to SP was concentration-dependent and reproducible. Thiorphan potentiated the secretory response to SP in a concentration-dependent fashion and phosphoramidon potentiated SP-induced secretion, whereas other inhibitors of proteinases and peptidases were without effects. These results suggest that substance P may regulate mucus secretion in ferrets, and that enkephalinase (dipeptidyl carboxypeptidase II, EC 3.4.24.11) in the airway degrades SP in a physiologically significant fashion, and thereby regulates peptide-induced secretion.
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PMID:Enkephalinase inhibitors potentiate substance P-induced secretion of 35SO4-macromolecules from ferret trachea. 243 22

Microvillar membranes derived from the brush border of the renal proximal tubule are very rich in peptidases. Pig kidney microvilli contain endopeptidase-24.11 associated with a battery of exopeptidases. The manner by which some neuropeptides are degraded by the combined attack of the peptidases of this membrane has been investigated. The contribution of individual peptidases was assessed by including inhibitors (phosphoramidon, captopril, amastatin and di-isopropyl fluorophosphate) with the membrane fraction when incubated with the peptides. Substance P, bradykinin and angiotensins I, II and III and insulin B-chain were rapidly hydrolysed by kidney microvilli. Oxytocin was hydrolysed much more slowly, but no products were detected from [Arg8]vasopressin or insulin under the conditions used for other peptides. The peptide bonds hydrolysed were identified and the contributions of the different peptidases were quantified. For each of the susceptible peptides, the main contribution came from endopeptidase-24.11 (inhibited by phosphoramidon). Peptidyl dipeptidase A (angiotensin-I-converting enzyme) was of less importance, even in respect of angiotensin I and bradykinin. When [2,3-Pro3,4-3H]bradykinin was also investigated at a lower concentration (20 nM), the conclusions in regard to the contributions of the two peptidases were unchanged. The possibility that endopeptidase-24.11 might attack within the six-residue disulphide-bridged rings of oxytocin and vasopressin was examined by dansyl(5-dimethylaminonaphthalene-1-sulphonyl)ation and by reduction and carboxymethylation of the products after incubation. Additional peptides were only observed after prolonged incubation, consistent with hydrolysis at the Tyr2-Ile3 and Tyr2-Phe3 bonds respectively. These results show that a range of neuropeptides are efficiently degraded by microvillar membranes and that endopeptidase-24.11 plays a key role in this process.
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PMID:Metabolism of neuropeptides. Hydrolysis of the angiotensins, bradykinin, substance P and oxytocin by pig kidney microvillar membranes. 243 10


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