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)

The ability of washed whole cells of Treponema denticola ATCC 35405 to hydrolyze (inactivate) substance P, bradykinin, and angiotensin I was studied. Substance P was attacked primarily at the Phe-8-Gly-9 bond by a chymotrypsin-like proteinase (CTLP), at Pro-4-Gln-5 by an endo-acting prolyl oligopeptidase (POPase), and at Gln-5-Gln-6 by an endopeptidase (FALGPA-peptidase). Bradykinin was cleaved at Phe-5-Ser-6 by the FALGPA-peptidase and at Pro-7-Phe-8 by the POPase. Angiotensin I was rapidly converted to angiotensin II by the CTLP, and both angiotensin I and angiotensin II were further hydrolyzed at Pro-7-Phe-8 by the POPase. All these enzymes were assumed to be cell associated and were easily extracted with a mild (0.05 to 0.1%) Triton X-100 treatment. Because it was conceivable that the hydrolysis of substance P at the Phe-8-Gly-9 bond was catalyzed by a CTLP described earlier (V.-J. Uitto, D. Grenier, E. C. S. Chan, and B. C. McBride, Infect. Immun. 56:2717-2722, 1988), the enzyme was purified to homogeneity by means of conventional fast protein liquid chromatography procedures. For kinetic studies, Phe-8(4-nitro)-substance P (NSP) (absorption maximum at 309.2 nm, epsilon = 545 M-1 cm-1) was synthesized to replace substance P as a substrate in kinetic studies. In reversed-phase chromatography, both NSP and substance P gave identical results with both whole cells and the purified enzyme. The CTLP has a mass of 95 kDa, and its activity is suggested to be based on an active seryl residue, on an active imidazole group, and on an active carboxyl group but not on metal cations. The enzyme hydrolyzes N-succinyl-L-Ala-L-Ala-L-Pro-L-Phe-p-nitroaniline (SAAPFNA, a typical chymotrypsin substrate) at a high rate and several proteins, such as calf thymus histone, human plasma fibrinogen, milk caseins, and gelatin. Among the substrates tested, substance P showed the highest affinity (Km = 0.22 mM) for the purified enzyme. Depending on conditions, clinically applicable chlorhexidine levels (3.2 mmol/liter, or 0.2%) strongly activated (up to fourfold) the hydrolysis of SAAPFNA by whole cells and the purified CTLP. The hydrolysis of NSP by whole cells and purified CTLP was slightly inhibited by chlorhexidine. The results demonstrated the versatility and the effectiveness of the outer membrane of T. denticola in occasioning a rapid breakdown and inactivation of human bioactive peptides and other peptidolytic catalyses.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of the chymotrypsin-like membrane-associated proteinase from Treponema denticola ATCC 35405 in inactivation of bioactive peptides. 754 86

In order to further develop structure-activity relationships and to get information about the biological active conformations we synthetized analogues tripeptide to the FR 113680 [Ac-Thr-D-Trp(CHO)-PheNMeBzl; Ac: acethyl], in which the phenylalanine residue was replaced by unconventional amino acids [1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); (3aS, 7aS)-octahydroindole-2-carboxylic acid (Oic); (S,S,S)-2-azabiciclo[3.3.0]octane-3-carboxylic acid (Aoc); 3-(1'-naphthyl)alanine (Nap); phenylglicine (Phg); thienylalanine (Thi)]. The biological activity of the peptides was performed on guinea pig ileum for neurokinin 1 (NK-1) and on rat colon for neurokinin 2 (NK-2). In particular, the replacement of the Phe3 by the Oic (8a) gave an higher antagonist activity in both NK-1 and NK-2 receptors, but no improvement in selectivity with respect to reference tripeptide (FR113680). The compound (8a) represent the first example of highly potent peptides that do not contain an aromatic amino acid of the third position as had been previously considered essential.
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PMID:Synthesis and biological activity of tripeptide FR113680 analogues containing unconventional amino acids. 757 38

Human neutrophils were isolated from blood and aseptic inflammatory exudates. The respiratory burst response was measured as superoxide (O2-) production by a microplate assay system and polarographically as oxygen consumption. Exudate cells exhibited a respiratory burst in response to n-formyl-methionyl-leucyl-phenyl-alanine (FMLP) that was two- to threefold higher than the burst exhibited by peripheral blood cells. The O2- production induced by substance P was also found to be fivefold higher in exudate cells, while the metabolic response to other stimulants such as concanavalin A (con A), phorbol-myristate acetate (PMA), NaF, and immunocomplexes was not primed. Serum-treated zymosan (STZ)-stimulated activity was primed by only 11%. In contrast, superoxide production in response to tumor necrosis factor-alpha (TNF) was decreased in exudate versus blood cells by about 50%. Therefore, the skin-window cells, compared to blood cells, appear to be at the same time primed, unmodified, and desensitized, according to the different stimulants employed.
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PMID:Factor-specific changes in oxidative burst response of human neutrophils in skin-window exudates. 767 71

The amyloid protein (beta A4) is found in the CNS of patients with Alzheimer's disease; however, the pathogenic role of this protein is not known. In the present study, a peptide fragment of beta A4 (beta A4 25-35; Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met-NH2), which contains the conserved C-terminal sequence of substance P (X-Gly-Leu-Met-NH2), and the neuropeptide substance P (SP) were examined for their ability to modulate nicotine-evoked secretion from cultured bovine adrenal chromaffin cells. Secretion of the released endogenous catecholamines was monitored by electrochemical detection after separation by HPLC. Secretion induced by 10(-5) M nicotine was inhibited by SP and beta A4 25-35. The IC50 of SP and beta A4 25-35 was 3 x 10(-6) and 3 x 10(-5) M, respectively. SP and beta A4 25-35 both protected against nicotine receptor desensitization. However, beta A4 25-35 was approximately 10-fold less effective than SP in its protective effect. The present work shows that beta A4 25-35 can mimic the modulatory actions of SP on the nicotinic response of cultured bovine chromaffin cells, i.e., inhibition of the nicotinic response and protection against nicotinic desensitization. These modulatory actions may be associated with changes in nicotinic receptor levels reported to occur in Alzheimer's disease.
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PMID:An amyloid peptide, beta A4 25-35, mimics the function of substance P on modulation of nicotine-evoked secretion and desensitization in cultured bovine adrenal chromaffin cells. 767 24

1. We compared the effects of two novel tachykinin receptor antagonists, FK888 (selective at the tachykinin NK1 receptor) and FK224 (dual antagonist at NK1 and NK2 tachykinin receptors) on stimulus-evoked airway plasma exudation, bronchoconstriction and systemic hypotension in guinea-pigs in vivo. Plasma exudation was induced by substance P (SP), synthetic tachykinin receptor agonists, platelet activating factor (PAF), electrical stimulation of the cervical vagus nerves or by inhalation of cigarette smoke. Changes in airway tone and in carotid artery blood pressure (BP) were induced by synthetic tachykinin agonists, PAF and vagal stimulation. 2. Both FK224 and FK888 dose-dependently inhibited SP-induced plasma exudation in the lower trachea and main bronchi (ID50 values respectively of 1.1 and 0.1 mumol kg-1 in lower trachea, and of 0.5 and 0.1 mumol kg-1 in main bronchi) with complete inhibition at both airway levels at 10 mumol kg-1 for FK224 and at 2 mumol kg-1 for FK888. 3. The NK1-selective tachykinin receptor agonist, [Sar9,Met(O2)11]substance P ([Sar]SP), induced plasma exudation, a response which was blocked by both FK888 and FK224. The NK2-selective agonist, [beta-Ala8]neurokinin A-(4-10) ([beta-Ala]NKA), did not induce plasma exudation: neither FK888 nor FK224 affected this lack of response to [beta-Ala]NKA. 4. [beta-Ala]NKA induced bronchoconstriction, a response which was blocked by FK224 but which was completely unaffected by FK888. [Sar]SP induced a small but significant bronchoconstriction which was completely inhibited by both tachykinin antagonists. 5. In animals pretreated with capsaicin to deplete sensory neuropeptides, PAF induced both plasma exudation and bronchoconstriction. Neither response to PAF was inhibited by either FK888 or FK224.6. Both FK888 and FK224 inhibited plasma exudation induced by vagus nerve stimulation or by cigarette smoke, with FK888 more potent than FK224.7. FK224 inhibited non-cholinergic bronchoconstriction induced by vagal stimulation, whereas FK888,at doses inhibiting vagally-induced plasma exudation, did not.8. Decreases in BP induced by SP or [Sar]SP were blocked by both FK888 and FK224. In contrast,neither antagonist had any significant inhibitory effect on the decrease in BP induced by vagal stimulation (in the presence of atropine) or PAF. [beta-Ala]NKA did not decrease BP and neither tachykinin antagonist had any significant effect on this lack of response.9. We conclude that in guinea-pig airways, plasma leakage induced by endogenous tachykinins is mediated predominantly via NK1-receptors, whereas bronchoconstriction is mediated predominantly via NK2-receptors. In addition, SP-evoked decreases in BP are also mediated via NK1 receptors, whereas the contribution of endogenous tachykinins to vagally-induced decreases in BP appears to be minimal.Development of selective tachykinin receptor antagonists will be important in understanding the involvement of tachykinins in airway physiology and pathophysiology, whereas potent dual tachykinin receptor antagonists such as FK224 may have greater therapeutic potential in certain airway diseases in which tachykinins have been implicated in pathogenesis, including asthma and chronic bronchitis associated with cigarette smoking.
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PMID:Effects of two novel tachykinin antagonists, FK224 and FK888, on neurogenic airway plasma exudation, bronchoconstriction and systemic hypotension in guinea-pigs in vivo. 768 42

Purification and structural characterization of tachykinins from rainbow trout (Oncorhynchus mykiss) intestine has demonstrated the presence of three different peptides related to the mammalian tachykinins: substance P, neurokinin A, and neuropeptide-gamma. The substance P- and the neurokinin A-related peptides present in the intestine are identical to the tachykinins previously isolated from the trout brain. The neuropeptide-gamma-related peptide (Ser-Ser-Ala-Asn-Pro-Gln-Ile-Thr-Arg-Lys-Arg-His-Lys-Ile-Asn-Ser-Phe- Val-Gly-Leu-Met-NH2), not previously identified in brain tissue, has the sequence of the neurokinin A-related tachykinin at its COOH-terminus. Both trout substance P and neurokinin A stimulated the motility of isolated trout intestinal muscle [pD2(-log of EC50) values 8.5 +/- 0.15 and 7.35 +/- 0.08, respectively] and the vascularly perfused trout stomach (pD2 values 9.63 +/- 0.23 and 8.18 +/- 0.23, respectively). Trout substance P was 14 times more potent than trout neurokinin A in the intestine and 28 times more potent in the stomach. The data suggest that receptors interacting with tachykinins in the trout gastrointestinal tract have a similar selectivity as the mammalian NK-1 receptor.
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PMID:Primary structures and effects on gastrointestinal motility of tachykinins from the rainbow trout. 769 88

1. NK1 and NK2 receptors have been characterized in guinea-pig lung membrane preparations by use of [125I-Tyr8]-substance P and [125I]-neurokinin A binding assays in conjunction with tachykinin-receptor selective agonists ([Sar9Met(O2)11]substance P for NK1 and [beta Ala8]neurokinin A (4-10) for NK2) and antagonists (CP-99,994 for NK1 and SR48968 for NK2). 2. The presence of high affinity, G-protein-coupled NK1 receptors in guinea-pig lung parenchymal membranes has been confirmed. The rank order of affinity for competing tachykinins was as predicted for an NK1 receptor: substance P = [Sar9Met(O2)11]substance P > substance P-methyl ester = physalaemin > neurokinin A = neurokinin B >> [beta Ala8]neurokinin A (4-10). The novel NK1 antagonist CP-99,994 has a Ki of 0.4 nM at this NK1 site. 3. In order to characterize [125I]-neurokinin A binding to guinea-pig lung, the number of [125I]-neurokinin A specific binding sites was increased 3-4 fold by purification of the parenchymal membranes over discontinuous sucrose gradients. The rank order of affinity determined for NK1- and NK2-receptor agonists and antagonists in competition for these sites showed that the majority (80%) of [125I]-neurokinin A specific binding was also to the NK1 receptor. 4. Under conditions where the guinea-pig lung parenchymal NK1 receptor was fully occupied by a saturating concentration of either [Sar9Met(O2)11]substance P (1 microM) or CP-99,994 (2.7 microM), residual [125I]-neurokinin A specific binding was inhibited in a concentration-dependent manner by both [beta Ala8]neurokinin A and SR48968. This result shows that the NK2 receptor is also present in these preparations. 5. Similar studies using guinea-pig tracheal membranes demonstrated that [125I]-neurokinin A specific binding was composed of a NK1-receptor component (60%), inhibited by both [Sar9Met(02)11]substance P and CP-99,994, and a significant NK2-receptor component, inhibited by both [beta Ala 8]neurokinin A andSR48968.6. In summary, these data demonstrate that guinea-pig lung parenchyma and guinea-pig trachea express both NK1 and NK2 receptors.
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PMID:Identification of both NK1 and NK2 receptors in guinea-pig airways. 769 56

We have investigated the interaction of fluorescent peptide ligands with the G protein-coupled receptor NK2 using novel spectrofluorometric approaches. Several heptapeptide antagonists of structure PhCO-Xaa-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 were labelled on position 1 (Xaa) with the environment-sensitive nitrobenzoxadiazole (NBD) probe, differing only in the length of the spacer between the NBD group and the peptide. Upon binding of the labelled antagonist to NK2 receptors stably expressed in Chinese hamster ovary (CHO) cells, an increase in NBD fluorescence was observed when the spacer length was less than 10 A. Collisional quenching experiments using iodide and Co2+ ions were performed to define the accessibility of the NBD group on bound ligands to the solvent. By comparing ligands with spacer arms of varying lengths, we found that the binding pocket is buried at a depth of 5-10 A. In contrast, N-terminally NBD-labelled agonists, decapeptide neurokinin A (NKA) or heptapeptide Nle10-NKA[4-10], bound to the NK2 receptor were accessible to the solvent. Binding of fluorescent ligands to the NK2 receptor was accompanied by an enhancement in the fluorescence anisotropy. The changes in fluorescence properties were used to determine the kinetic parameters of antagonist binding and dissociation. These results indicate that the binding site on the NK2 receptor for the amino-terminal end of the heptapeptide antagonists is buried in the hydrophobic pocket of the receptor protein and clearly distinct from the binding site for the amino-terminal end of agonists, which is accessible to the solvent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Probing the binding domain of the NK2 receptor with fluorescent ligands: evidence that heptapeptide agonists and antagonists bind differently. 769 62

GR159897 ((R)-1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-4-methoxy-4- [(phenylsulfinyl)methyl]piperidine) is a novel, highly potent and selective non-peptide antagonist at tachykinin NK2 receptors. GR159897 inhibited binding of the NK2 receptor antagonist radioligand [3H]cyclohexylcarbonyl-Gly-Ala-(D)Trp-Phe-NMe2 ([3H]GR100679) to human ileum NK2 receptors transfected into Chinese hamster ovary cells (pKi 9.5) and to rat colon membranes (pKi 10.0). GR159897 was a competitive antagonist of contractions induced by the NK2 receptor agonist [Lys3,Gly8-R-gamma-lactam-Leu9]neurokinin A-(3-10) (GR64349) in guinea-pig trachea (pA2 8.7), and had negligible activity at human NK1 receptors transfected into Chinese hamster ovary cells (pKi 5.3), NK1 receptors in guinea-pig trachea (pKB < 5) or NK3 receptors in guinea-pig cerebral cortex (pKi < 5). In vivo, in the anaesthetised guinea-pig, GR159897 (0.12 mg.kg-1 i.v.) potently antagonised bronchoconstriction induced by GR64349 (dose-ratio = 28), with a long duration of action (3 h). GR159897 should be a useful tool for studying the physiological and pathophysiological role of tachykinin NK2 receptor activation.
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PMID:GR159897, a potent non-peptide antagonist at tachykinin NK2 receptors. 771 68

A peptidase, isolated from rat testes, is inhibited by 1 mM o-phenanthroline, 1 microM N-(1-(R,S)-carboxyl-3-phenylpropyl)-Ala-Ala-Phe-p-aminobenzoate, and 6 mM Pro-Ile, properties similar to those ascribed to endopeptidase 24.16. The enzyme hydrolyzes dynorphin A-8, neurotensin 1-13, angiotensin I, and substance P. Kinetic analysis of a series of angiotensin I analogs showed that substitutions at P-1, P-1', or P-2' had little effect on Km or Kcat. Variation of peptide size with a series of dynorphin A peptides showed chain length to be significant. The peptidase cleaved dynorphin A-8 at both Leu5-Arg6 and Arg6-Arg7, and neurotensin 1-13 at Pro10-Tyr11 and Arg8-Arg9. In contrast, rat endopeptidase 24.16 cleaves dynorphin A-8 at Gly4-Leu5 and Leu5-Arg6, and neurotensin 1-13 only at Pro10-Tyr11. These findings, as well as the observation that endopeptidase 24.16 exhibits a considerably higher affinity for Pro-Ile, Ki = 90 microM, indicates the peptidase isolated in this study is related to, but distinct from, rat endopeptidase 24.16. We propose that this new endopeptidase be referred to as endopeptidase 24.16B, while the originally described enzyme be referred to as endopeptidase 24.16A.
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PMID:Endopeptidase 24.16B. A new variant of endopeptidase 24.16. 773 Mar 8


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