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)

A soluble tripeptidylaminopeptidase has been isolated from human post-mortem cerebral cortex by anion exchange, hydrophobic interaction and size-exclusion chromatography. From gel filtration studies the active enzyme can exist in both high molecular weight (M(r) > 10(6) and smaller forms. The enzyme hydrolyses Ala-Ala-Phe-7-amido-4-methylcoumarin with a pH optimum of around 7.5 and Km of 148 microM. It did not hydrolyse N-succinyl-Ala-Ala-Phe-7-amido-4-methylcoumarin, aminoacyl- or dipeptidyl-7-amido-methylcoumarins and was not inhibited by bestatin. The enzyme was inhibited by phenylmethylsulphonyl-fluoride, 3,4-dichloroisocoumarin, N-hydroxymercuriphenyl-sulphonic acid and N-ethylmaleimide showing that its activity is serine and cysteine dependent. The purified enzyme released tripeptides from several naturally occurring neuropeptides with quite broad specificity. Cholecystokinin octapeptide, angiotensin III and neurokinin A were the most rapidly hydrolysed. Peptides with Pro residues around the point of cleavage were not hydrolysed.
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PMID:Purification and characterization of tripeptidylpeptidase-II from post-mortem human brain. 839 12

A metalloendopeptidase (MEP) isolated from rabbit liver microsomes with substrate specificity for peptides containing Arg at the P1 and P4 positions has recently proved to be identical to soluble angiotensin-binding protein present in the cytosol. Here we describe the peptide-degrading specificity of MEP, determined using various bioactive peptides and novel fluorogenic substrates for the enzyme. MEP degraded oligopeptides, including bradykinin, alpha-neoendorphin, bovine adrenal medulla dodecapeptide, substance P, bombesin, neurotensin, and alpha-endorphin, but not polypeptides such as reduced lysozyme and histone H4, hence, MEP probably belongs to the family of endo-oligopeptidases. It cleaved most preferentially at the -Phe-Ser- bond of bradykinin (kcat/Km = 2.8 x 10(4) M-1.S-1) but did not cleave high molecular weight and low molecular weight kininogens, the precursors of bradykinin. MEP did not cleave angiotensin I, dynorphin A 1-13, somatostatin, and luteinizing hormone-releasing hormone, some of which are good substrates for metalloendopeptidase-24.15, metalloendopeptidase-24.16, N-arginine dibasic convertase, and yeast endopeptidase-24.15 related peptidase. An active site-directed inhibitor of metalloendopeptidase-24.15, N-[1-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate also had no effects on the amidolytic activity of MEP. Based on the cleavage sites of bioactive peptides and processing sites of vitamin K-dependent proproteins, intramolecularly quenched fluorogenic peptide substrates were newly synthesized. Among the thirteen substrates used, the most reactive was 2-aminobenzoyl-Ala-Arg-Val-Arg-Arg-Ala- Asn-Ser-2,4-dinitroanilinoethylamide (kcat/Km = 9.3 x 10(5) M-1.S-1). An angiotensin antagonist, [Sar1, Ala8]-angiotensin II, inhibited hydrolysis of the substrate by MEP in a competitive manner (Kl = 7.6 microM). MEP cleaved oligopeptides even on the carboxyl side of proline residue and these peptides are resistant to hydrolysis by the cytosol-derived proteasome, therefore MEP may participate in the catabolism of oligopeptides in the cytosol, together with other endo-oligopeptidases.
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PMID:Substrate specificity of rabbit liver metalloendopeptidase and its new fluorogenic peptide substrates. 857 4

We exposed A/J mice to several challenge aerosols and measured gas trapped within excised lungs by quantitating their buoyancy in saline (Archimedes' principle). The temporal stability of the excised lung gas volume (ELGV) measurement was also examined. ELGV increased in a dose proportional manner with increasing concentrations of methacholine and reached a maximum of 338 +/- 33% above vehicle-exposed controls. The A/J mice were 100 times more responsive to aerosol methacholine compared to hyporesponsive C3H/HeJ mice. Aerosol challenges of U-46619, a thromboxane A2 mimetic, and serotonin resulted in a 40% and 135% increase in ELGV's versus their controls, respectively. ELGV's were not increased after aerosols of leukotriene C4, histamine, substance P, N-formyl-methionyl-leucyl-phenyl-alanine and platelet activating factor. Both normal (filtered air-exposed) and hyperinflated (methacholine-exposed) excised lungs lost about 10% of their initial volume by 30 min and 40-65% of initial volume by 4 h. Occlusion of the trachea in either group did not affect the total gas lost, suggesting that majority of the gas loss was via transpleural diffusion. We conclude that determination of ELGV in mice, when performed soon after challenge testing, is a simple, rapid and reliable estimate of airway obstruction.
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PMID:Effect of bronchoconstrictive aerosols on pulmonary gas trapping in the A/J mouse. 861 Feb 13

We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the peptide N2-[(4R)-4-hydroxy-1-[(1-methyl-1H-indol-3-yl) carbonyl]-L-prolyl]-N-methyl-N-(phe-nylmethyl)-3-(2-naphthyl)-L-al aninamide (FK888) modified on the (2-naphthyl)-L-alanine and the [(1-methyl-1H-indol-3-yl)carbonyl] moieties. The compounds were tested on guinea pig ileum for NK-1, rat colon for NK-2 and rat portal vein for NK-3 receptors. The two most potent peptides of this series, 1b and 2b, were selective for the NK-2 receptor (pA2 = 7.5 and 7.3, respectively).
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PMID:Modification of the potent peptide FK888 with unusual aminoacids: effects on activity on neurokinin receptors. 868 42

Group B streptococci were recently reported to possess a cell-associated collagenase. Although the enzyme hydrolyzed the synthetic collagen-like substrate N-(3-[2-furyl]acryloyl)-Leu-Gly-Pro-Ala, we found that neither the highly purified enzyme nor crude group B streptococcal cell lysate solubilized a film of reconstituted rat tail collagen, an activity regarded as obligatory for a true collagenase. We cloned and sequenced the gene for the enzyme (pepB). The deduced amino acid sequence showed 66.4% identity to the PepF oligopeptidase from Lactococcus lactis, a member of the M3 or thimet family of zinc metallopeptidases. The group B streptococcal enzyme also showed oligopeptidase activity and degraded a variety of small bioactive peptides, including bradykinin, neurotensin, and peptide fragments of substance P and adrenocorticotropin.
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PMID:Characterization of PepB, a group B streptococcal oligopeptidase. 875 83

We examined the effect of two des-Met-bombesin analogues, [(CH3)2CHCO-His-Trp-Ala-Val-D-Ala-His-Leu-NHCH3] (ICI 216140) and [D-Phe6,des-Met14]bombesin(6-14) ethylamide (DPDM-bombesin ethylamide), on neuromedin B-induced Ca2+ and [3H]arachidonate release in BALB 3T3 cells transfected with human neuromedin B receptors. ICI 216140 and DPDM-bombesin ethylamide both stimulated Ca2+ mobilisation in a concentration-dependent manner but were less potent and efficacious than neuromedin B. BIM 23042 [D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2], a selective neuromedin B antagonist and [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, a broad-spectrum peptide receptor antagonist inhibited neuromedin B-, ICI 216140 and DPDM-bombesin ethylamide-induced Ca2+ release. Pretreatment of cells with either des-Met-bombesin analogue attenuated neuromedin B-induced Ca2+ elevations, suggesting similar agonist-sensitive Ca2+ pools. The pharmacological profiles revealed from the [3H]arachidonate assay were similar, although ICI 216140 was less potent and efficacious than DPDM-bombesin ethylamide. The data suggest that ICI 216140 and DPDM-bombesin ethylamide behave as agonists at the neuromedin B receptor, perhaps as a consequence of neuromedin B receptor overexpression.
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PMID:Pharmacological profiles of two bombesin analogues in cells transfected with human neuromedin B receptors. 881 45

The purpose of present study was to determine whether peptidase activity affects the release of substance P (SP) and calcitonin gene-related peptide (CGRP) from spinal cord slices. When slices were exposed to various inhibitors of endopeptidase 24.11, the resting and capsaicin-stimulated release of SP were less than 0.04% and 0.20% total content per minute, respectively. Resting CGRP release was approximately 0.10% and stimulated release was 0.40%. The combination of 20 microM bacitracin, 100 microM phenylalanylalanine (Phe-Ala), and 50 microM p-chloromercuriphenylsulfonic acid (PCMS) significantly increased both resting and stimulated release of SP and CGRP at least two- or threefold. Doubling the concentration of PCMS and Phe-Ala did not further improve peptide release. These results demonstrate that recovery of peptides released from spinal cord slices is dependent in part on activity of multiple peptidases in the tissues.
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PMID:Peptidase inhibitors improve recovery of substance P and calcitonin gene-related peptide release from rat spinal cord slices. 882 7

We have purified and characterized human brain endopeptidase 3.4.24.16. The enzyme behaved as a 72 kDa protein and belonged to the metalloprotease family. Human endopeptidase 3.4.24.16 cleaved neurotensin at a unique site at the Pro10-Tyr11 bond, leading to the formation of neurotensin(1-10) and neurotensin(11-13). The kinetic parameters displayed by human endopeptidase 3.4.24.16 towards a series of natural neuropeptides indicated that bradykinin was the most efficiently proteolysed. Angiotensin I, dynorphins 1-8 and 1-9 and substance P also behaved as good substrates while neuromedin N, angiotensin II, leucine and methionine enkephalin and neurokinin A resisted degradation by human endopeptidase 3.4.24.16. We have purified the porcine counterpart of endopeptidase 3.4.24.16 and compared its ability to cleave neurotensin with that of the enzyme from human origin. It appeared that, besides a major production of neurotensin(1-10), an additional formation of neurotensin(1-8) was observed with the pig enzyme, suggesting a cleavage of neurotensin not only at the Pro10-Tyr11 bond but also at the Arg8-Arg9 peptidyl bond. The latter cleavage appeared reminiscent of endopeptidase 3.4.24.15 since this peptidase was reported to cleave neurotensin at the Arg8-Arg9 bond. Our study indicated that neurotensin(1-10) formation by porcine endopeptidase 3.4.24.16 could be potently blocked with the selective endopeptidase 3.4.24.16 dipeptide inhibitor Pro-Ile without interfering with neurotensin(1-8) formation. By contrast, the formation of the latter product was highly potentiated by dithiothreitol and inhibited by the endopeptidase 3.4.24.15 inhibitor Cpp-Ala-Ala-Tyr-pAB, two effects that were not observed for neurotensin(1-10) production. Altogether, our results indicate that porcine endopeptidase 3.4.24.16 cleaves neurotensin at a unique site, leading to the formation of neurotensin(1-10) and that the production of neurotensin(1-8) is due to contaminating endopeptidase 3.4.24.15.
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PMID:Purification and characterization of human endopeptidase 3.4.24.16. Comparison with the porcine counterpart indicates a unique cleavage site on neurotensin. 886 56

The potassium salt of a chemically stabilized dipeptide, {1-[4-(1 H-tetrazol-5-yl)butyl]indol-3-yl}carbonyl-Hyp-Nal-N(methyl)-Bzl , (Hyp = (R)-4-hydroxy-L-proline; Nal = 3-L-(beta-naphthyl)-alanine), S18523, is described as a new water-soluble, potent and selective NK1 receptor antagonist. The low molecular weight antagonist (M(r) = 736) displays nanomolar potency (pA2 = 9.6) in the rabbit vena cava (NK1) bioassay and nanomolar affinity (pKi = 9.1) on the human NK1 receptor expressed by lymphoblastoma cells. It is devoid of mu-opiate affinity (Ki > 10(-4) M with respect to tritiated Tyr-DAla-Gly-MePhe-Gly-ol), has negligible calcium-channel affinity (estimated Ki = 2.6 x 10(-5) M, with respect to isradipine) and does not cause peritoneal mast-cell degranulation. S18523 has strong antinociceptive effects in three classical pain tests in vivo both by i.v. and p.o. routes. The dipeptide potently antagonizes bronchoconstriction provoked by exogenous substance P in the guinea-pig and acts longer than the non-peptide antagonist CP99994, when administered as aerosol. Finally, S18523 displays antiinflammatory properties, since it dose-dependently inhibits substance P-induced plasma extravasation both in the bladder (ID50 = 0.18 mg/kg i.v.) and bronchi (ID50 = 0.14 mg/kg i.v.) of the guinea-pig.
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PMID:A water-soluble, stable dipeptide NK1 receptor-selective neurokinin receptor antagonist with potent in vivo pharmacological effects: S18523. 888 65

The topography of the binding site of a monoclonal anti-substance P antibody directed toward the C-terminal pentapeptide of substance P, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, was analyzed further using a wide range of constrained analogues of substance P. Results obtained in the present study show the following: (a) The binding subsites of Phe7 and Phe8 are large and deep, accommodating various side chains, including nonaromatic amino acids. (b) In contrast, the binding pockets for Gly-Leu-Met-NH2 appear more restrictive. Consequently, five residues in the peptide are necessary for the high binding affinity to the antibody, the C-terminal tripeptide determining the binding specificity. These data, which appear to contradict those previously published, illustrate the limits of conclusions drawn from studies generally carried out using exclusively Ala-substituted peptides. In addition, the present results indicate that the topography of the binding site of this monoclonal antibody differs from that of the specific substance P neurokinin-1 receptor, in agreement with the differences observed in the fine specificities of these two substance P binding macromolecules.
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PMID:Use of conformationally constrained peptides for a topographical analysis of the combing site of a monoclonal anti-substance P antibody. 892 27


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