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)

The Drosophila melanogaster diphenol oxidase (DOX) A2-encoding gene (Dox-A2) is involved in catecholamine metabolism, melanin formation and sclerotization of the cuticle. Insect phenol oxidases (POX) are well studied biochemically, but not genetically and molecularly. The Dox-A2 (2-53.9) gene is the first insect POX-encoding gene to be cloned and sequenced. It encodes a protein product unique among currently known POX. The deduced protein, however, exhibits extensive similarity (58-81%) to the mouse mast cell tum- antigen, P91A [Lurquin et al., Cell 58 (1989) 293-303] and may identify the normal mouse protein as a DOX.
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PMID:Drosophila melanogaster diphenol oxidase A2: gene structure and homology with the mouse mast-cell tum- transplantation antigen, P91A. 190 80

In the absence of any specific literature on the isolation of RNA from mast cells, our initial attempts established that unusual measures would be needed to prepare acceptable yields of high quality RNA from peritoneal mast cells of normal adult rats. Accordingly, we developed procedures for the isolation and characterization of RNA from rat peritoneal mast cells (PMC) and basophilic leukemia cells (RBL). The significant components of the procedures include: separation and removal of mast cell granules to minimize contamination of RNA with proteins and proteoglycans; use of bentonite in phenol extractions; and repetition of extractions and precipitation. The amounts of total RNA extracted from PMC were about 15% of those from RBL, although the percentage mRNA of total RNA in PMC and RBL was similar (1.8 and 2.0%). Ribosomal RNA banding patterns in agarose gel electrophoresis and in vitro translation experiments indicate that the isolated RNA can be employed for analysis of molecular mechanisms of mast cell function and heterogeneity.
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PMID:Isolation and in vitro translation of mRNA from rat peritoneal mast cells and rat basophilic leukemia cells. 318 93

The phenolic group of active site residue Tyr-248 in carboxypeptidase A has a pKa value of 10.06, as determined from the pH dependence of its rate of nitration by tetranitromethane. The decrease in enzyme activity (kcat/Km) in alkaline solution, characterized by a pKa value of approximately 9.0 (for cobalt carboxypeptidase A), is associated with the protonation state of an imidazole ligand of the active-site metal ion, as indicated by a selective pH dependence of the 1H NMR spectrum of the enzyme. Inhibition of the cobalt-substituted enzyme by 2-(1-carboxy-2-phenylethyl)phenol and its 4,6-dichloro- and 4-phenylazo-derivatives confirms that the decrease in enzyme activity (kcat/Km) in acidic solution, characterized by a pKa value of 5.8, is due to the protonation state of a water molecule bound to the active-site metal ion in the absence of substrate. Changes in the coordination number of the active-site metal ion are seen in its visible absorption spectrum as a consequence of binding of the phenolic inhibitors. Conventional concepts regarding the mechanisms of the enzyme are brought into question.
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PMID:pK values for active site residues of carboxypeptidase A. 337 37

The observation of binding synergism has been successfully extended to include carboxypeptidases A and B. The behaviour of these two enzymes follows the same pattern previously found for three other Zn-proteases. Thus in all cases examined, the affinity of a suitable Zn-ligand is increased in the presence of a compound (specificity probe) which contains the key structural features of specific substrates. A bifunctional ligand such as phosphonoacetate is particularly useful for generating synergism in both carboxypeptidases. Presumably the carboxylate moiety binds to the C-terminal recognition site while the other functional group interacts with the metal ion. Several basic compounds (e.g. methyl guanidine) act as effective specificity probes for carboxypeptidase B while phenol and other hydrophobic substances serve this purpose in carboxypeptidase A. The above phenomenon appears to be a mechanism designed to enhance catalytic efficiency through a substrate-induced conformational change. We postulate that there is a requirement for at least one ionizable group at the active site. The proposed mechanism keeps this group in the correct ionization state in the presence of water and increases its reactivity after exclusion of water by substrate binding. We suggest the term xerophilic shift for this process. Since proton transfer is a common process in enzyme reactions, the xerophilic-shift mechanism may play a similar role in many instances. It should therefore be possible to detect binding synergism in a wide variety of enzymes.
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PMID:General occurrence of binding synergism in zinc proteases and its possible significance. 826 43

Competitive inhibition constants Ki for a series of phenol-ring-substituted derivatives of alpha-(2-hydroxyphenyl)benzenepropanoic acid have been ascertained by observing their influence on the catalytic hydrolysis of a peptide substrate by the zinc enzyme carboxypeptidase A. The pH-dependence of Ki shows that binding is maximal between two pKa values: one is that of the phenol group of the inhibitor, and the other uniformly has a value of 6, the pKa of a Zn(2+)-bound water molecule on the enzyme in the absence of substrate or inhibitor. This is the dependence expected if phenolate binds to the Zn2+ displacing its bound H2O/HO-. A log-log plot of the dissociation constants for the productive forms of inhibitor plus enzyme versus the acid dissociation constants of the phenolic residues in the inhibitors yields a straight line with a slope of +0.76. This number indicates that the active-site metal ion has special capacity for dispersing negative charge, such as builds up on the oxygen atom of a carboxamide group undergoing nucleophilic addition.
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PMID:Fluxionate Lewis acidity of the Zn2+ ion in carboxypeptidase A. 842 57

The antiasthmatic drug enprofylline was the first known selective, though not potent, A(2B) antagonist. On the basis of structure-activity relationships (SARs) of xanthine derivatives, we designed a novel selective adenosine A(2B) receptor antagonist, 3-isobutyl-8-pyrrolidinoxanthine (IPDX), with potency greater than that of enprofylline. IPDX displaced [3H]ZM241385 ([3H]4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a]-[1,3,5]triazin-5-ylamino]ethyl)phenol) from human A(2B) adenosine receptors with a K(i) value of 470 +/- 2 nM and inhibited A(2B)-dependent cyclic AMP (cAMP) accumulation in human erythroleukemia (HEL) cells with a K(B) value of 625 +/- 71 nM. We found that IPDX was more selective than enprofylline toward human A(2B) receptors. It was 38-, 55-, and 82-fold more selective for human A(2B) than for human A(1) (K(i) value of 24 +/- 8 microM), human A(2A) (K(B) value of 36 +/- 8 microM), and human A(3) (K(i) value of 53 +/- 10 microM) adenosine receptors, respectively. IPDX inhibited NECA (5'-N-ethylcarboxamidoadenosine)-induced interleukin-8 secretion in human mast cells (HMC-1) with a potency close to that determined for A(2B)-mediated cAMP accumulation in HEL cells, thus confirming the role of A(2B) adenosine receptors in mediating human mast cell activation. Since adenosine triggers bronchoconstriction in asthmatic patients through human mast cell activation, IPDX may become a basis for the development of new antiasthmatic drugs with improved properties compared with those of enprofylline. Our data demonstrate that IPDX can be used as a tool to differentiate between A(2B) and other adenosine receptor-mediated responses.
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PMID:Inhibition of human mast cell activation with the novel selective adenosine A(2B) receptor antagonist 3-isobutyl-8-pyrrolidinoxanthine (IPDX)(2). 1170 49

Phenol (PHE) and hydroquinone (HQ) are metabolites of benzene that affect leukocytes after solvent intoxication. Hence, we investigated the effects of PHE or HQ exposure on neutrophil mobilization during an inflammatory response. Male Wistar rats received intraperitoneal injections of PHE, HQ or vehicle only and assays were performed 24 h after the last dose. Quantifications of bone marrow or circulating leukocytes showed that only HQ exposure induced neutrophilia, probably due to the accelerated mobilization from the bone marrow compartment, since reduced numbers of segmented cells in the last phase of maturation were detected there. Intravital microscopy showed that circulating leukocytes of HQ-exposed rats increased their rolling behavior and adherence to the mesenteric postcapillary venule wall in vivo. The enhanced leukocyte-endothelium interaction was not dependent on microvascular reactivity or perivascular mast cell degranulation. Instead, it was the result of neutrophil activation, demonstrated by a decrease in L-selectin and an increase in beta2 integrin expression on neutrophil membranes. This pattern of neutrophil activation may have contributed to the higher number of neutrophils in the subcutaneous inflammatory response of HQ-exposed rats after oyster glycogen injection. Taken together, our results indicate that HQ exposure alters neutrophil mobilization, which results in an exacerbated response after an injury. Although PHE is endogenously metabolized to HQ, PHE exposure only induced an increment in rolling behavior, which was not sufficient to alter the inflammatory response.
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PMID:Effect of in vivo phenol or hydroquinone exposure on events related to neutrophil delivery during an inflammatory response. 1642 81

Two phenylpropanoids, 1-allyl-3,5-dimethoxy-4-(3-methyl-but-2-enyloxy)benzene ( 4) and 4-allyl-2,6-dimethoxy-3-(3-methyl-2-butenyl)phenol ( 6), and two phytoquinoids, 4 R-(-)-illicinone-A ( 7) and 2 S,4 R-(-)-illicinone-B ( 8), isolated from plants of the ILLICIUM species significantly inhibited histamine release from rat basophilic leukemia (RBL-2H3) cells stimulated with A23187. Furthermore, these compounds caused a decline in TNF-alpha levels in culture supernatants of RBL-2H3 cells following treatment with A23187. The results indicate that these compounds might be useful as anti-inflammatory agents against mast cell-mediated inflammatory diseases.
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PMID:Anti-inflammatory activity of phenylpropanoids and phytoquinoids from Illicium species in RBL-2H3 cells. 1753 71

The present study was designed to investigate the antidiarrhoeal potential of 50% ethanolic extract of Cinnamomum tamala on experimentally induced castor oil diarrhoea, gastric emptying of phenol red meal, gastrointestinal transit of charcoal meal and in vitro mast cell degranulation activity. C. tamala extract (25, 50 and 100 mg/kg, orally) produced a dose-dependent reduction in the total amount of faecal matter in castor oil-induced diarrhoea. The mean distance travelled by charcoal meal at 50 and 100 mg/kg of extract showed a significant reduction in the secretion of gastrointestinal fluid accumulation by 32.5-65.0%. The Na(+) and K(+) concentrations on castor oil-induced fluid accumulation showed a greater inhibitory effect on Na(+) levels than on K(+) concentrations. C. tamala significantly reduced the lipid peroxidation (P < 0.001) and increased the catalase (P < 0.01) activity in comparison to the castor oil-induced groups. C. tamala leaf extract did not show any significant effect at a higher dose (15 mg/ml) on mast cell degranulation. However, the extract in the dose of 5 and 10 mg/ml conferred significant mast cell protective action (P < 0.001). The percentage of eugenol in extract is 3.8% w/w, and total tannin is 247.5 mg/g. The result indicates the Indian spice C. tamala is useful for diarrhoea.
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PMID:Antidiarrhoeal activity of the standardised extract of Cinnamomum tamala in experimental rats. 1849 39

Lung parenchymal strips isolated from ovalbumin-sensitized rats manifest a mast cell-dependent, biphasic contraction when challenged with allergen. The first phase is mediated by the release of preformed 5-HT while the second phase is dependent on de novo synthesis of leukotrienes. Sphingosine 1-phosphate (S1P) is a sphingolipid metabolite which is readily generated in mast cells and has been demonstrated to be an important regulator of allergen-induced mast cell activation. We have used the parenchymal strip to explore the role of sphingosine 1-phosphate and the S1P(2) receptor in the two components of the acute response to allergen. Lung parenchymal strips were prepared from Brown Norway rats actively sensitized to ovalbumin. The strips were set up in organ baths and contractile responses measured isometrically. The inhibitors of sphingosine kinase, D-erythro-NN-dimethylsphingosine (dimethylsphingosine) and 4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol (SKI-II) inhibited concentration-dependently both phases of the contractile response induced by 0.1 microg ml(-1) ovalbumin. The effects were seen at concentrations similar to those which inhibit the purified enzyme and were selective in that neither the contractile response to adenosine nor that to 5-hydroxytryptamine was affected. JTE-013 (a selective S1P(2) receptor antagonist) also blocked the response to ovalbumin (0.1 microg ml(-1)). However, the concentrations of JTE-013 required (microM) were substantially higher than its affinity for the S1P(2) receptors (nM). However, when tested against a lower concentration of ovalbumin (0.03 microg ml(-1)), JTE-013 inhibited the response with nM potency. These data demonstrate the importance of S1P and the S1P(2) receptor as regulators of allergen-induced activation of mast cells in their natural environment in the rat lung.
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PMID:Role of sphingosine-1-phosphate (S1P) and the S1P(2) receptor in allergen-induced, mast cell-dependent contraction of rat lung parenchymal strips. 1963 35


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