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), which can degrade low molecular weight opioid peptides, has been reported in both peripheral vasculature and in the CNS. Thus, we have studied the metabolism of opioid peptides by membrane-bound aminopeptidase M derived from cerebral microvessels of hog and rabbit. Both hog and rabbit microvessels were found to contain membrane-bound aminopeptidase M. At neutral pH, microvessels preferentially degraded low molecular weight opioid peptides by hydrolysis of the N-terminal Tyr1-Gly2 bond. Degradation was inhibited by amastatin (I50 = 0.2 microM) and bestatin (10 microM), but not by a number of other peptidase inhibitors including captopril and phosphoramidon. Rates of degradation were highest for the shorter peptides (Met5- and Leu5-enkephalin) whereas beta-endorphin was nearly completely resistant to N-terminal hydrolysis. Km values for the microvascular aminopeptidase also decreased significantly with increasing peptide length (Km = 91.3 +/- 4.9 and 28.9 +/- 3.5 microM for Met5-enkephalin and Met5-enkephalin-Arg6-Phe7, respectively). Peptides known to be present within or in close proximity to cerebral vessels (e.g., neurotensin and substance P) competitively inhibited enkephalin degradation (Ki = 20.4 +/- 2.5 and 7.9 +/- 1.6 microM, respectively). These data suggest that cerebral microvascular aminopeptidase M may play a role in vivo in modulating peptide-mediated local cerebral blood flow, and in preventing circulating enkephalins from crossing the blood-brain barrier.
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PMID:Metabolism of opioid peptides by cerebral microvascular aminopeptidase M. 287 69

The major site of hydrolysis was the Gly8-Leu9 bond. Angiotensin converting enzyme (peptidyl dipeptidase A, EC 3.4.15.1) from pig kidney hydrolysed substance P releasing the C-terminal tripeptide Gly-Leu-MetNH2 but failed to hydrolyse neurokinin B. Pig brain striatal synaptic membranes hydrolysed neurokinin B producing a similar pattern of products as did endopeptidase-24.11. Substantial inhibition of this activity was achieved with the selective inhibitor phosphoramidon. A combination of phosphoramidon and bestatin abolished the hydrolysis of neurokinin B by synaptic membranes. Thus, a bestatin-sensitive aminopeptidase may play a role in the synaptic metabolism of neurokinin B in addition to endopeptidase-24.11. This aminopeptidase appears to be distinct from aminopeptidase N (EC 3.4.11.2).
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PMID:Neurokinin B is hydrolysed by synaptic membranes and by endopeptidase-24.11 (enkephalinase) but not by angiotensin converting enzyme. 299 26

Vasoactive peptides contain a high proportion of proline residues which make them resistant to hydrolysis by many peptidases. However, post proline cleaving enzyme (PPCE; EC 3.4.21.26), a proline specific endopeptidase which specifically hydrolyzes internal peptide bonds on the carboxyl side of proline residues, has been shown to inactivate numerous vasoactive peptides including angiotensins, kinins, substance P, vasopressin and oxytocin. In order to determine whether PPCE could be involved in vascular metabolism of vasoactive peptides, we carried out localization and characterization studies of PPCE-like activity in hog aorta and mesenteric artery. PPCE was assayed fluorometrically at pH 7.0 using the specific PPCE substrate CBZ-Gly-Pro-4-methyl-coumarinylamide. The subcellular distribution of vascular PPCE was essentially the same as that of the cytosolic marker enzyme lactic dehydrogenase (LDH). PPCE was enriched six-fold in the cytosolic fraction (11.4 +/- 2.7 units/mg) and unlike the plasma membrane-bound proline specific exopeptidase dipeptidyl-(amino)peptidase IV (DAP IV; EC 3.4.14.5), little or no activity could be detected in the microsomal or plasma membrane fractions. Similar to PPCE characterized from other sites, vascular PPCE was stabilized and activated by dithiothreitol and EDTA, and inhibited by DFP, p-chloromercuriphenyl sulfonic acid, L-1-tosylamido-2-phenylethylchloromethyl ketone, Cu++, Ca++, and Zn++. Vascular PPCE was unaffected by inhibitors of trypsin and kallikrein (Aprotinin, ABTI), aminopeptidase M (bestatin, amastatin), neutral endopeptidase (phosphoramidon), angiotensin I converting enzyme (captopril) or carboxypeptidase N (MERGETPA). These data demonstrate that PPCE is present in vascular endothelium and/or smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular, post proline cleaving enzyme: metabolism of vasoactive peptides. 354 18

Dipeptidylpeptidase IV (EC 3.4.14.5), an enzyme which metabolizes substance P, is present in crude homogenates of hog mesenteric artery and aorta. Its subcellular localization is closely correlated with the plasma membrane marker enzyme 5'-nucleotidase (EC 3.1.3.5) in addition to the kinin and angiotensin metabolizing enzymes angiotensin I converting enzyme (EC 3.4.15.1) and aminopeptidase M (EC 3.4.11.2). The highest level of dipeptidylpeptidase IV is found on the surface membrane-enriched fraction and is immunologically identical to the kidney brush border-bound enzyme. Vascular dipeptidylpeptidase IV sequentially removes the N-terminal Arg1-Pro2 and Lys3-Pro4 dipeptides of substance P and exposes the biologically active C-terminal heptapeptide product to rapid degradation by vascular aminopeptidases.
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PMID:Mesentery vascular metabolism of substance P. 618 94

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

Aminopeptidase N purified from human placenta actively hydrolyzed various immunomodulating peptides from their N-terminus such as splenopentin, thymopentin, thymic humoral factor gamma 2, tuftsin and rigin in vitro. Aminopeptidase N also actively hydrolyzed neuropeptide hormones (met-enkephalin, somatostatin and neurokinin A) and vasoactive peptides (lysyl-bradykinin and angiotensin III) from their N-terminus. In addition, angiotensin II, secretin, thymopoietin II peptide fragment, motilin, endothelin-I and insulin were tested for hydrolysis by aminopeptidase N. Km and Vmax values for the N-terminal amino acid, Thr, a liberation from tuftsin were 267 microM and 8.33 mumol/min/mg protein, respectively. L-Leucyl-p-nitroanilidase activity in the human placental membrane fraction was almost completely neutralized by anti-aminopeptidase N antibody. Our present study suggests that possible roles for surface enzyme aminopeptidase N in the human placenta would be to down-regulate the action of immunomodulating peptides as well as vasoactive and neuropeptide hormones, and to control both immunology and endocrinology of pregnancy.
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PMID:Possible action of human placental aminopeptidase N in feto-placental unit. 790 13

Crude membrane fractions prepared from rabbit gastric fundic muscle degraded vasoactive intestinal polypeptide (VIP) with an average specific activity of 0.96 nmol/min/mg protein at 37 degrees C, pH 7.5, and at [S]o = 0.05 mM. The relative activities towards [Leu5]enkephalin, substance P, VIP, and neurotensin were approximately 7.7, 2.0, 1.0, and 0.54, respectively. The VIP degradation was inhibited by metal chelators EDTA and o-phenanthroline. CaCl2 at 0.3-1.0 mM enhanced VIP degradation up to twofold. Phosphoramidon, captopril, and bestatin, the specific inhibitors for endopeptidase-24.11, angiotensin-converting enzyme, and aminopeptidase M, respectively, did not affect VIP degradation significantly. However, the complex mixtures of VIP fragments generated implicates action of multiple peptidases including the aforementioned three peptidases and other unidentified peptidase(s).
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PMID:Degradation of vasoactive intestinal polypeptide by rabbit gastric smooth muscle membranes. 800 38

The tachykinin peptide agonists neurokinin A and [beta Ala8]neurokinin A-(4-10), and the NK2 tachykinin receptor-selective antagonists MEN 10,208, MEN 10,207, MEN 10,282, MEN 10,376 and R396 were assayed in the isolated rabbit pulmonary artery and isolated hamster trachea in the absence and in the presence of the aminopeptidase inhibitor amastatin (10 microM for 30 min). The affinity of MEN 10,208 in the rabbit pulmonary artery was markedly reduced in the presence of amastatin (pKB values from 7.47 to 5.94), while it was unchanged in the hamster trachea. Neither neurokinin A, [beta Ala8]neurokinin A-(4-10), nor the other antagonists were affected by pretreatment with amastatin in either bioassay. The results obtained in the rabbit pulmonary artery show that MEN 10,208 is degraded by local amastatin-sensitive enzymes (possibly aminopeptidase M), which may convert the linear octapeptide MEN 10,208 to the heptapeptide MEN 10,207 by removing the N-terminal Thr from the amino acid sequence of MEN 10,208. The present results are discussed in relation to a previously reported heterogeneity between NK2 receptors of the rabbit and bovine species, and show amastatin to be a new tool for the classification of tachykinin receptors with peptide ligands.
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PMID:Amastatin interferes with the antagonist properties of MEN 10,208 in the rabbit pulmonary artery but not in the hamster trachea. 839 54

In addition to their well characterized effects at dopamine receptors, neuroleptic drugs have been shown to affect the level and in vitro metabolism of neuropeptides. In the present study, the effect of acute and subchronic administration of the neuroleptic haloperidol and the nonselective, dopamine agonist apomorphine on neuropeptidase activity was determined in regional, rat brain P2 membranes. Subchronic administration of haloperidol decreased the activity of aminopeptidase N in the frontal cortex and caudate-putamen. In contrast, subchronic administration of apomorphine increased aminopeptidase N activity in the frontal cortex and caudate-putamen. Neutral endopeptidase 24.11 also was affected differentially in the caudate-putamen, but both subchronic haloperidol and apomorphine decreased neutral endopeptidase 24.11 activity in the frontal cortex. Metalloendopeptidase 24.15 activity was decreased in the caudate-putamen after acute haloperidol and increased in the frontal cortex after acute apomorphine administration; however, no effect was noted after subchronic administration of either drug. Angiotensin converting enzyme was not affected by any treatment. Therefore, neuroleptic-induced alterations in aminopeptidase N, neutral endopeptidase 24.11 and metalloendopeptidase 24.15 activity may account for previously reported alterations in neuropeptide degradation. In view of the interaction between mesocorticolimbic dopamine neurons and neuropeptides, e.g., substance P, neurotensin and enkephalins, neuroleptic-induced alterations in the activities of neuropeptidases, and thus neuropeptide metabolism can, in turn, play a role in modulating midbrain dopaminergic activity.
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PMID:Haloperidol and apomorphine differentially affect neuropeptidase activity. 861 7

Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK-1-receptor antagonist. Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580. Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin. It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP. In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of bradykinin are concealed by the effects of the other mediators.
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PMID:Influence of several peptidase inhibitors on the pro-inflammatory effects of substance P, capsaicin and collagenase. 893 67


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