Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eosinophil migration toward a concentration gradient of a chemotactic factor is regulated at four levels. Diverse immunologic pathways generate stimuli with eosinophil chemotactic activity, including the complement products C5a and a fragment of C3a and the peptide products of mast cells and basophils activated by IgE-mediated reactions, such as eosinophil chemotactic factor of anaphylaxis (ECF-A) and other oligopeptides. The intrinsic preferential leukocyte activity of the chemotactic stimuli represents the second level of modulation, with ECF-A and other mast cell-derived peptides exhibiting the most selective action on eosinophils. The third level of control of eosinophil chemotaxis is composed of inactivators and inhibitors of chemotactic stimuli and is exemplified by degradation of C5a by anaphylatoxin inactivator or chemotactic factor inactivator and of ECF-A by carboxypeptidase-A or aminopeptidases. The activity of ECF-A is uniquely suppressed by equimolar quantities of its NH2- terminal tripeptide substituent, presumably by eosinophil membrane receptor competition. Factors comprising the fourth level of regulation, which alter eosinophil responsiveness to chemotactic stimuli, include the chemotactic factors themselves, through deactivation; nonchemotactic inhibitors such as the COOH-terminal tripeptide substituent of ECF-A, the neutrophil-immobilizing factor (NIF), the phagocytosis-enhancing factor Thr-Lys-Pro-Arg, and histamine at concentrations greater than 400 ng/ml; and nonchemotactic enhancing principles represented by ascorbate and by histamine at concentrations of 30 ng/ml or less. Local concentrations of eosinophils called to and immobilized at the site of a hypersenitivity reaction may express their regulatory functions by degrading the chemical mediators elaborated including histamine, slow-reacting substance of anaphylaxis (SRS-A), and platelet-activating factor (PAF) by way of their content of histaminase, arylsulfatase B, and phospholipase D, respectively. Immunologic pathways may thus provide the capability for early and specific host defense reactions with a later influx of eosinophils preventing irreversible local tissue alterations or distant organ effects.
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PMID:Modulation of human eosinophil polymorphonuclear leukocyte migration and function. 79 10

We have recently found presence of a high concentration of a novel type of kinin, hydroxyprolyl3-bradykinin (Hyp3-BK) in human tumor ascites in addition to conventional bradykinin (BK). Because of their potential physiological activity, it is of interest to know how these bradykinins can be degraded in ascites. Degradation of two synthetic kinins, BK and Hyp3-BK, added to the ascitic fluid from patients with ovarian carcinoma and hepatoma, were analyzed by reversed phase HPLC. Both kinins were degraded into their desArg9-BK or -Hyp3-BK and desPhe8-Arg-9-BK or -Hyp3-BK products following incubation with the ascitic fluid. The rate of the degradation of BK and Hyp3-BK was the same. The formation of desArg9-BK was completely inhibited by kininase I inhibitor, while the formation of desPhe8-Arg9-BK was not completely inhibited by a kininase II inhibitor. The degradation of both kinins was inhibited completely by EDTA. The results indicate the presence of other metalloprotease(s) which cleaves kinins in the ascitic fluid, in addition to kininase I and kininase II. The carboxypeptidase A and carboxypeptidase B inhibitor, benzyl malic acid, failed to block degradation of both kinins. A rapid cleave of Phe-Arg into Phe and Arg was also found in the ascitic fluid. Thus, the major degradation products of kinins in the ascitic fluid were demonstrated to be either desArg9-BK or Hyp3-BK, desPhe8-Arg9-BK or -Hyp3-BK, phenylalanine and arginine. Lysyl-BK and lysylhydroxyprolyl3-BK were rapidly converted into BK and hydroxyprolyl3-BK by the ascitic fluid.
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PMID:Degradation pathway of kinins in tumor ascites and inhibition by kininase inhibitors: analysis by HPLC. 216 Jan 86

A novel method for the synthesis of histargin and its analogs is described. It includes two kinds of N-alkylation reactions that prevent the formation of side products. The inhibition of enzymes by these compounds was also measured. Some of the compounds strongly inhibited carboxypeptidase B, carboxypeptidase A, carboxypeptidase N (kininase I), and angiotensin converting enzyme.
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PMID:Synthesis of histargin and related compounds and their inhibition of enzymes. 320 75

C5a is an 11,000-Da complement-derived inflammatory glycoprotein that has been shown to mediate inflammatory reactions in vitro as well as in vivo in human skin. The C5a degradation product, C5a des Arg, is rapidly formed after exposure of C5a to serum carboxypeptidase N and may represent the relevant C5-derived inflammatory peptide in vivo. To examine the biologic activity of human C5a des Arg in vivo and to compare it with that seen with human C5a, we purified and characterized homogeneous preparations of human C5a and C5a des Arg and injected them intradermally into seven normal volunteers. C5a des Arg exhibited biochemical and biologic properties in vitro that were different from those of C5a. When injected into human skin, C5a des Arg was less potent than C5a, in respect to both minimal dose eliciting wheal and flare reactions and maximal wheal and flare elicited at a given dose, but C5a des Arg still elicited cutaneous wheal and flare reactions at physiologically relevant concentrations. Histologically, C5a des Arg skin test sites showed dense polymorphonuclear neutrophil-rich infiltrates associated with leukocytoclasis, dermal mast cell degranulation, and endothelial cell swelling. These were virtually indistinguishable from reactions elicited by C5a and occurred with concentrations attainable in vivo. Cutaneous wheal and flare reactions elicited by either C5a or C5a des Arg were partially inhibited by H1 antihistamines but were unaffected by selected nonsteroidal anti-inflammatory agents.
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PMID:A direct in vivo comparison of the inflammatory properties of human C5a and C5a des Arg in human skin. 335 4

We have compared the digestion of bradykinin, lysyl bradykinin, and kinin degradation products by carboxypeptidases N, B and A (CPN, CPB and CPA). Carboxypeptidase N removed the C-terminal arginine from bradykinin or lysyl bradykinin to leave the des-Arg derivative of each, and no further degradation occurred regardless of enzyme concentration or time of incubation. However, both CPB and CPA degraded the des-Arg derivatives to remove the C-terminal phenylalanine. The inhibitory effect of phosphate ions upon this activity of CPB (but not CPA) suggests that CPA may be responsible for the formation of free phenylalanine seen upon degradation of kinins in plasma or serum. However, angiotensin converting enzyme degraded des-Arg9-bradykinin in plasma or serum prior to such Phe removal to yield the pentapeptide Arg-Pro-Pro-Gly-Phe and the tripeptide Ser-Pro-Phe. We demonstrated that CPB degraded Arg-Pro-Pro-Gly-Phe but not Ser-Pro-Phe; this reaction was also inhibited by phosphate ions. Carboxypeptidase A, on the other hand, liberated Phe from both peptides in phosphate-buffered saline and accounted, at least in part, for the free phenylalanine detected. Carboxypeptidase N did not digest the aforementioned pentapeptide or tripeptide. It is clear that carboxypeptidase B and carboxypeptidase A had overlapping activities, depending upon the substrate tested, and were distinguished by the effects of different ionic environments. We further suggest a role for carboxypeptidases other than CPN in the degradation of kinins in human plasma or serum.
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PMID:Studies of the digestion of bradykinin, lysyl bradykinin, and kinin-degradation products by carboxypeptidases A, B, and N. 371 39

The complement cleavage product C5a is a potent agonist of different leukocyte types and also has anaphylatoxic properties through the release of mediators by basophils and tissue mast cells. C5a is very rapidly degraded by serum carboxypeptidase N which cleaves the functionally important carboxy-terminal arginine, generating C5desarg, a chemotactic agonist with little mast cell-activating ability. Here we show that natural human C5adesarg is still a trigger for basophil mediator release superior to other endogenous IgE-independent agonists such as monocyte chemotactic protein (MCP)-1, interleukin (IL)-8, C3a and platelet-activating factor. On a molar basis C5adesarg is only one order of magnitude less potent and about half as efficacious as C5a at inducing basophil degranulation. Priming of basophils with either IL-3, IL-5, granulocyte-macrophage-colony-stimulating factor (GM-CSF) or nerve growth factor (NGF) (with comparable efficacies, but different potencies: IL-3 > NGF > IL-5 > GM-CSF) enhanced histamine release and conditioned the cells to produce large amounts of leukotriene C4 (LTC4), which is not generated by basophils exposed to C5adesarg alone. The efficacy of C5a and C5adesarg at inducing histamine and LTC4 release by primed basophils was similar. Thus, C5adesarg is a stable inducer of release of inflammatory mediators by human basophils, particularly in primed cells, and complement may, therefore, play a role in immediate-type hypersensitivity diseases in allergic late-phase reactions.
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PMID:The degradation product of the C5a anaphylatoxin C5adesarg retains basophil-activating properties. 751 76

We compared angiotensin I-converting enzyme (ACE) and carboxypeptidase A (CPA), two zinc metallopeptidases, for the hydrolysis of the usual ACE synthetic substrate benzoylglycyl-histidyl-leucine (HHL) investigating the possible interference by CPA in the determination of ACE activity in biological fluids. Both purified enzymes hydrolyse HHL in a radiochemical assay with the same optimal pH, a characteristic divalent metal requirement, a close similar behavior against inhibitors of other metallopeptidases, such as enkephalinase and kininase I, and the involvement of arginine and lysine residues in their active site. Conversely, CPA does not show the other catalytic properties of ACe, i.e. chloride dependence, low Km for HHL, inhibition by specific synthetic ACE inhibitors and antibody, also hydrolysis of the other ACE substrate furylacryloylphenylalanyl-glycyl-glycine (FAPGG). We advise the use of ACE inhibitors to validate ACE measurement with HHL or, alternatively, FAPGG, which is a more specific substrate for ACE, must be preferred, although the poor sensitivity of the spectrophotometric assay with this substrate limits its use to blood samples.
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PMID:Carboxypeptidase A hydrolyses benzoylglycyl-histidyl-leucine but not furylacryloyl-phenylalanyl-glycyl-glycine, two usual substrates for angiotensin I-converting enzyme. 758 46

We have investigated the contractile effect of bradykinin (BK) in guinea pig lung in vitro. BK induces a dose-related contraction of lung parenchymal strips which is increased significantly in the presence of 10(-5) M captopril (an angiotensin converting enzyme inhibitor) or 10(-5) M DL-thiorphan (a neutral endopeptidase inhibitor). The kininase I inhibitor, DL-2-mercaptomethyl-3-guanidino-ethylthiopropionic acid (MGTPA), has no effect on the BK-induced contraction. BK is more potent in contracting parenchymal lung strips than other contractile agents (histamine, carbachol and substance P), however the BK-induced maximal contraction is lower than those obtained with histamine and carbachol. The B1 agonist, des-Arg9-BK, does not contract lung parenchymal strips. The new BK B2 receptor antagonists (Hoe 140, NPC 17731 and NPC 17761), which possess binding affinities in the nanomolar range, inhibit the BK-induced contractile response in a dose-dependent manner. The BK-induced contraction was unaffected by propranolol, atropine, tetrodotoxin, capsaicin pre-treatment, triprolidine, methysergide, Ro 19-3704 and N omega-nitro-L-arginine-methyl-ester (L-NAME), excluding the involvement of nervous pathways, preformed mast cell mediators, platelet-activating factor and nitric oxide. However, indomethacin, a cyclooxygenase inhibitor, AA-861, a 5-lipoxygenase inhibitor, and furegrelate, a thromboxane A2 synthase inhibitor, decreased the contractile response to BK, suggesting that both cyclooxygenase and 5-lipoxygenase products are involved in this contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin-induced contraction of guinea pig lung in vitro. 799 Sep 78