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)

Dipeptidyl peptidase I (DPPI) is a cysteine protease found in many tissues, including the lung. Major cell types expressing DPPI in vitro include myelomonocytic cells, cytotoxic T cells, and mast cells. After activation and degranulation, cytotoxic T cells and mast cells secrete DPPI. With a goal of clarifying possible roles for DPPI in lung diseases, we sought to identify cells expressing DPPI in lung tissue, hypothesizing that lung mast cells are major producers of DPPI and that secreted DPPI cleaves extracellular matrix proteins. To address these hypotheses, we used immunohistochemical techniques to localize DPPI in normal dog airways, lung, and cultured mast cells, and we used purified DPPI to examine cleavage of matrix-associated proteins in vitro. We found that mast cells are the major identifiable source of DPPI in airways and that macrophages are the major source in alveoli. Within mast cells, DPPI localizes to cytoplasmic granules. We also found that DPPI endoproteolytically cleaves the extracellular matrix proteins fibronectin and collagen types I, III, and IV. The finding of DPPI in airway mast cells and its cleavage of matrix proteins suggest the possibility that DPPI plays a role in mast cell-mediated turnover of matrix proteins and in airway remodeling of chronic airway diseases such as asthma.
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PMID:Dipeptidyl peptidase I cleaves matrix-associated proteins and is expressed mainly by mast cells in normal dog airways. 1065 39

Dipeptidyl peptidase I (DPPI) is the sole activator in vivo of several granule-associated serine proteases of cytotoxic lymphocytes. In vitro, DPPI also activates mast cell chymases and tryptases. To determine whether DPPI is essential for their activation in vivo, we used enzyme histochemical and immunohistochemical approaches and solution-based activity assays to study these enzymes in tissues and bone marrow-derived mast cells (BMMCs) from DPPI +/+ and DPPI -/- mice. We find that DPPI -/- mast cells contain normal amounts of immunoreactive chymases but no chymase activity, indicating that DPPI is essential for chymase activation and suggesting that DPPI -/- mice are functional chymase knockouts. The absence of DPPI and chymase activity does not affect the growth, granularity, or staining characteristics of BMMCs and, despite prior predictions, does not alter IgE-mediated exocytosis of histamine. In contrast, the level of active tryptase (mMCP-6) in DPPI -/- BMMCs is 25% that of DPPI +/- BMMCs. These findings indicate that DPPI is not essential for mMCP-6 activation but does influence the total amount of active mMCP-6 in mast cells and therefore may be an important, but not exclusive mechanism for tryptase activation.
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PMID:Dipeptidyl peptidase I is essential for activation of mast cell chymases, but not tryptases, in mice. 1127 33

An immobile artificial metallopeptidase having a well-defined active site was constructed on the backbone of cross-linked polystyrene by adjoining a guanidinium moiety to the Cu(II) complex of a tetraaza ligand. The catalyst (CABP) and intermediate polymers were characterized by elemental analysis, IR, inductively coupled plasma measurement, electron probe microanalysis, test for primary amines, binding of Cu(II) ion, and complexation of p-nitrobenzoate ion. CABP effectively catalyzed amide hydrolysis of carboxyl-containing N-acyl amino acids. The catalytic rate of CABP in the hydrolysis of unactivated amides was comparable to that of the catalytic antibody with the highest peptidase activity reported to date. It is proposed that the guanidinium moiety of CABP recognizes the carboxylate anion of the substrate whereas the Cu(II) center participates in the cleavage of the amide bond of the complexed substrate. Several characteristic features of carboxypeptidase A were reproduced by CABP: catalytic action of the metal ion, participation of guanidinium in substrate recognition, hydrolysis of small unactivated amides, and substrate selectivity toward amide bonds adjacent to a carboxylate group.
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PMID:Artificial peptidase with an active site comprising a Cu(II) center and a proximal guanidinium ion. A carboxypeptidase A analogue. 1153 36

Dipeptidyl peptidase III (DPP III) (EC 3.4.14.4), which has a HELLGH-E (residues 450-455, 508) motif as the zinc binding site, is classified as a zinc metallopeptidase. The zinc dissociation constants of the wild type, Leu(453)-deleted, and E508D mutant of DPP III at pH 7.4 were 4.5 (+/-0.7) x 10(-13), 5.8 (+/-0.7) x 10(-12), and 3.2 (+/-0.9) x 10(-10) M, respectively. The recoveries of the enzyme activities by the addition of various metal ions to apo-DPP III were also measured, and Co(2+), Ni(2+), and Cu(2+) ions completely recovered the enzyme activities as did Zn(2+). The dissociation constants of Co(2+), Ni(2+), and Cu(2+) ions for apo-DPP III at pH 7.4 were 8.2 (+/-0.9) x 10(-13), 2.7 (+/-0.3) x 10(-12), and 1.1 (+/-0.1) x 10(-14) M, respectively. The shape of the absorption spectrum of Co(2+)-DPP III was very similar to that of Co(2+)-carboxypeptidase A or Co(2+)-thermolysin, in which the Co(2+) is bound to two histidyl nitrogens, a water molecule, and a glutamate residue. The absorption spectrum of Cu(2+)-DPP III is also very similar to that of Cu(2+)-thermolysin. The EPR spectrum and the EPR parameters of Cu(2+)-DPP III were very similar to those of Cu(2+)-thermolysin but slightly different from those of Cu(2+)-carboxypeptidase A. The five lines of the superfine structure in the perpendicular region of the EPR spectrum in Cu(2+)-DPP III suggest that nitrogen atoms should coordinate to the cupric ion in Cu(2+)-DPP III. All of these data suggest that the donor set and the coordination geometry of the metal ions in DPP III, which has the HExxxH motif as the metal binding site, are very similar to those of the metal ions in thermolysin, which has the HExxH motif.
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PMID:Characterization of the metal-substituted dipeptidyl peptidase III (rat liver). 1157 Aug 86

Mast cell chymases and tryptases exhibit an intriguing but potentially confusing variety of forms and functions. Thanks to recent genetic and biochemical advances, a clearer picture of phylogenetic and functional relationships in this large group of mammalian enzymes is emerging. Furthermore, there is increasing appreciation of the diversity of these enzymes among human populations. In humans, there appears to be just one mast cell chymase but multiple expressed tryptases, some of which are allelic variants and others of which are products of separate gene loci. New biological tools, including the dipeptidyl peptidase I (DPPI)-null mouse in which the entire class of mast cell chymases appears to be functionally knocked out, are helping to clarify the importance and specific roles of these most abundant of secreted mast cell proteins.
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PMID:New developments in the genetics and activation of mast cell proteases. 1221 7

An inhibitor of the metallo-ectoenzyme, pyroglutamyl aminopeptidase II (PPII), a thyrotropin releasing hormone-specific peptidase, was identified by screening extracts from marine species of the Cuban coast-line belonging to the phylla Chordata, Echinodermata, Annelida, Mollusca, Cnidaria, Porifera, Chlorophyta and Magnoliophyta. Isolation of the inhibitor (HcPI), from the marine annelide Hermodice carunculata, was achieved by trichloroacetic acid treatment of the aqueous extract, followed by ion-exchange chromatography on DEAE Sephacel, gel filtration on Sephadex G-25 and reverse phase-HPLC. HcPI had a small apparent molecular weight (below 1000 Da) and was not a peptide. It inhibited rat PPII (a membrane preparation with 8.5mg protein/ml) with an apparent K(i) of 51 nM. HcPI did not inhibit serine (trypsin, chymotrypsin, elastase and dipeptidyl aminopeptidase IV), cysteine (papain, bromelain and pyroglutamyl aminopeptidase I), aspartic (pepsin and recombinant human immunodeficiency virus 1 protease (HIV1-PR)) nor other metallo proteinases (collagenase, gelatinase, angiotensin converting enzyme, aminopeptidase N and carboxypeptidase A). HcPI was non-toxic and active in vivo. Intraperitoneal injection of HcPI reduced mouse pituitary and brain PPII activity. Potency of the effect was higher in hypophysis and hypothalamus than in other brain regions. Intrathecal administration to male rats reduced PPII activity in the spinal cord. In conclusion we have identified a specific inhibitor of PPII that is the first M1 family zinc metallo-peptidase inhibitor isolated from marine invertebrates. It may be useful for elucidating the in vivo role of PPII in the pituitary and central nervous system.
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PMID:Purification of a specific inhibitor of pyroglutamyl aminopeptidase II from the marine annelide Hermodice carunculata. in vivo effects in rodent brain. 1459 39

The mast cell proteases tryptase and chymase are synthesised as inactive precursors, but are stored and secreted as active enzymes. The cysteinyl protease dipeptidyl peptidase I (DPPI, cathepsin C) can activate the corresponding proenzymes in cell-free systems, but it is unknown whether it fulfils this role within the intact cell. We, therefore, tested the effect the DPPI-selective inhibitor Gly-Phe diazomethyl ketone (Gly-Phe-CHN(2)) on the tryptic and chymotryptic activity of the human mast cell-like cell line, HMC-1, and monitored any changes in the amount of immunodetectable enzymes by flow cytometry. Culture in Gly-Phe-CHN(2) produced a significant decrease in tryptase activity in cell lysates within 24hr and further decreases during continued culturing to 216 hr with periodic replenishment of Gly-Phe-CHN(2)-containing media. Flow cytometry showed no significant change in the levels of immunoreactive tryptase. In contrast, chymotryptic activity in treated cells did not differ significantly from untreated cells at any time point. Treatment of 216 hr cell lysates with DPPI revealed significant amounts of activatable protryptase in Gly-Phe-CHN(2)-treated cells, but not in controls, whereas activatable prochymotryptic activity was found in both treated and control cells. Chymase was detected immunologically, though small differences in substrate specificity and molecular mass were observed. These results strongly suggest that DPPI plays a role in the activation of tryptase, but not of the predominant chymotryptic activity of HMC-1 cells. As inhibitors of tryptase have proven efficacious in models of allergic disease, these results also indicate that inhibitors of DPPI might provide an additional point of therapeutic control.
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PMID:Inhibition of dipeptidyl peptidase I in the human mast cell line HMC-1: blocked activation of tryptase, but not of the predominant chymotryptic activity. 1460 49

The mechanism(s) of bradykinin-induced bronchoconstriction was investigated in the Brown Norway (BN) rat model of allergic asthma. Bronchoconstrictor responses to i.v. bradykinin in BN rats were maximally augmented 24 h following challenge with allergen and declined at later time points. Histological evaluation of the inflammatory status of the lungs after ovalbumin (OA) challenge showed a marked inflammatory response, which was maximal at 24 h and declined thereafter. However, pretreatment with budesonide did not inhibit the augmented bronchoconstrictor response to bradykinin 24 h after allergen challenge. The selective B1 receptor agonist, Lys-[desArg9]-BK had no bronchoconstrictor effects, whereas the selective B2 receptor antagonist, HOE 140, abolished the response to bradykinin in OA-challenged animals. The augmented response to bradykinin was not affected by methysergide, indomethacin, disodium cromoglycate, iralukast, the 5-lipoxygenase inhibitor, CGS8515, or the NK2 receptor antagonist, SR48968. It was, however, partially inhibited by atropine both in saline- and OA-challenged animals. Pretreatment with captopril and thiorphan markedly potentiated responses to bradykinin both in saline- and OA-challenged animals. Thus, augmentation of the bronchoconstrictor response to bradykinin occurs in actively sensitised BN rats 24 h after challenge with OA and is associated with marked pulmonary inflammation. The response is entirely B2 receptor mediated and approximately 50% of the response is cholinergic. However, mast cell activation, the products of the cyclooxygenase or 5-lipoxygenase pathways and tachykinins are not involved. Peptidase inhibition mimics the effect of allergen challenge on the bronchoconstrictor response to bradykinin and it remains possible that the mechanism of the augmented response to bradykinin following allergen challenge involves downregulation of peptidase activity as a consequence of the inflammatory response.
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PMID:Airway hyperresponsiveness to bradykinin induced by allergen challenge in actively sensitised Brown Norway rats. 1472 5

Sepsis is a common, life-threatening disease for which there is little treatment. The cysteine protease dipeptidyl peptidase I (DPPI) activates granule-associated serine proteases, several of which play important roles in host responses to bacterial infection. To examine DPPI's role in sepsis, we compared DPPI(-/-) and DPPI(+/+) mice using the cecal ligation and puncture (CLP) model of septic peritonitis, finding that DPPI(-/-) mice are far more likely to survive sepsis. Outcomes of CLP in mice lacking mast cell DPPI reveal that the absence of DPPI in mast cells, rather than in other cell types, is responsible for the survival advantage. Among several cytokines surveyed in peritoneal fluid and serum, IL-6 is highly and differentially expressed in DPPI(-/-) mice compared with DPPI(+/+) mice. Remarkably, deleting IL-6 expression in DPPI(-/-) mice eliminates the survival advantage. The increase in IL-6 in septic DPPI(-/-) mice, which appears to protect these mice from death, may be related to reduced DPPI-mediated activation of mast cell tryptase and other peptidases, which we show cleave IL-6 in vitro. These results indicate that mast cell DPPI harms the septic host and that DPPI is a novel potential therapeutic target for treatment of sepsis.
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PMID:Mast cell dipeptidyl peptidase I mediates survival from sepsis. 1496 72

In vivo efficacy of novel anticancer agents has been hindered by the inability to deliver effective concentrations of drugs to tumors. The use of macromolecules such as antibodies and polymers for enzyme delivery to tumors has revealed that catalyzing the conversion of a nontoxic prodrug into its cytotoxic form can generate an effective level of cytotoxic agents at tumor sites. This study primarily focuses on the synthesis and characterization of methoxypoly(ethylene glycol)-modified carboxypeptidase A (CPA) for solid tumor targeting. The molecular weight of CPA has been successfully altered from 35 to 40-50 kDa via attachment of a defined number of mPEG moieties. Relatively pure mPEG-CPA conjugates containing one, two, and three mPEG chains were obtained at preparative scale quantities through controlled PEGylation followed by fractionation that involved size-exclusion chromatography. An enhancement in kinetic properties including k(cat) and k(cat)/K(m) towards hippuryl-L-phenylalanine (hipp-L-phe) was observed in mPEG-CPA conjugates. An increase in the V(m) appeared to be responsible for this enhancement. The attachment of mPEG to CPA substantially improved the stability of the enzyme with respect to the specific peptidase activity toward the model substrate. This finding is particularly important in the development of a novel CPA/methotrexate-alpha-peptide system in solid tumor chemotherapy.
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PMID:Methoxypoly(ethylene glycol)-conjugated carboxypeptidase A for solid tumor targeting: part I: synthesis and characterization. 1586 40


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