Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human tryptase is uniquely regulated by its association with heparin and resists inhibition by biological protease inhibitors. The effects of pH and B12, an IgG anti-tryptase mAb, on cleavage of the synthetic substrate tosyl-Gly-Pro-Lys-p-nitroanilide and of the biological substrate fibrinogen by tryptase were examined. Tosyl-Gly-Pro-Lys-pnitroanilide cleavage was optimal at neutral pH and was inhibited by the B12 mAb at acidic and neutral pH values. At pH 7.5, inhibition was reversible and noncompetitive. In contrast, the optimal pH for tryptase to cleave fibrinogen was acidic. B12 dramatically enhanced the rate and extent that tryptase cleaved all three fibrinogen subunits at pH 6.0 to 6.5, but inhibited these activities at neutral pH. Major fibrinogen cleavage fragments generated at acidic pH by the B12:tryptase complex were identical with those made by plasmin. Thus, at acid pH, tryptase alone destroyed the ability of fibrinogen to clot, while the B12:tryptase complex increased the rate of fibrinogenolysis and also generated the anticoagulant, fragment D. The acidic pH optimum for tryptase fibrinogenolysis may direct this activity to tissue sites of inflammation. A putative biological equivalent to B12 would limit tryptase fibrinogenolytic activity at sites of neutral pH, such as blood, but would augment activity at acidic sites.
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PMID:Human tryptase fibrinogenolysis is optimal at acidic pH and generates anticoagulant fragments in the presence of the anti-tryptase monoclonal antibody B12. 931 53

Serum tryptase was measured with the B12 and G5 antibody-based immunoassays in 25 adult patients with mastocytosis and in 18 controls. Twelve patients had uncomplicated cutaneous mastocytosis (urticaria pigmentosa) and 13 had urticaria pigmentosa with systemic symptoms. Tryptase levels were compared with histamine turnover estimated as urinary excretion of the main histamine metabolite tele-methylimidazoleacetic acid. Elevated B12 tryptase levels (> 20 microg/L) were found in most mastocytosis patients, including five of eight patients with only cutaneous manifestations who had a low urinary histamine metabolite excretion. This indicated a higher sensitivity for diagnosing mild mastocytosis on the basis of levels of serum tryptase as opposed to urinary methylimidazoleacetic acid. However, the serum B12 tryptase assay could not differentiate between urticaria pigmentosa patients with and without systemic disease: the measurement of histamine metabolite excretion probably reflects the mast cell burden more accurately. Serum G5 tryptase levels were generally low in both controls and mastocytosis patients.
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PMID:Serum tryptase measured with B12 and G5 antibody-based immunoassays in mastocytosis patients and its relation to histamine turnover. 989 55

Tryptase is a specific marker of mast-cell activation and plays a part in the pathophysiology of various allergic diseases including asthma, but little is known of the spillover of this enzyme into the systemic circulation. Therefore, we measured serum levels of mast-cell-derived tryptase in 21 patients with mild to moderate asthma and 20 healthy, subjects, using a B12 monoclonal antibody-based immunofluoroassay that detects both monomers and tetramers of alpha- and beta-tryptases. There was a good correlation between serum and sputum tryptase levels, and, compared with healthy subjects (1.68 +/- 0.31 ng/ml), asthma patients had higher concentrations of serum tryptase (atopic asthma, 4.18 +/- 0.95 ng/ml, p = 0.022; nonatopic asthma, 3.93 +/- 0.82 ng/ml, p = 0.031). Although serum tryptase levels did not correlate with asthma symptom scores, peak expiratory flow, or forced expiratory volume in 1 s, they positively correlated with mast-cell and eosinophil counts (p = 0.041 and p = 0.025, respectively) and eosinophil cationic protein contents (p = 0.029) in induced sputum. These results suggest that serum tryptase detected with B12 antibody is a marker of allergic airway inflammation in asthma.
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PMID:Serum B12 tryptase level as a marker of allergic airway inflammation in asthma. 1209 81

Since serum tryptase levels are elevated in some patients with myeloproliferative disorders, we examined their utility in identifying a subset of patients with hypereosinophilic syndrome (HES) and an underlying myeloproliferative disorder. Elevated serum tryptase levels (> 11.5 ng/mL) were present in 9 of 15 patients with HES and were associated with other markers of myeloproliferation, including elevated B12 levels and splenomegaly. Although bone marrow biopsies in these patients showed increased numbers of CD25+ mast cells and atypical spindle-shaped mast cells, patients with HES and elevated serum tryptase could be distinguished from patients with systemic mastocytosis and eosinophilia by their clinical manifestations, the absence of mast cell aggregates, the lack of a somatic KIT mutation, and the presence of the recently described fusion of the Fip1-like 1 (FIP1L1) gene to the platelet-derived growth factor receptor alpha gene (PDGFRA). Patients with HES and elevated serum tryptase were more likely to develop fibroproliferative end organ damage, and 3 of 9 died within 5 years of diagnosis in contrast to 0 of 6 patients with normal serum tryptase levels. All 6 patients with HES and elevated tryptase treated with imatinib demonstrated a clinical and hematologic response. In summary, elevated serum tryptase appears to be a sensitive marker of a myeloproliferative variant of HES that is characterized by tissue fibrosis, poor prognosis, and imatinib responsiveness.
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PMID:Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. 1452 92

Inhaled chloroform anesthesia was introduced in 1847. Soon thereafter, the chemical reactivity of aerobically heated chloroform permitted John Snow and Claude Bernard to do seminal experiments in the assay of drug levels and drug metabolism. However, it was not widely appreciated until a clinical mishap in 1899 that thermal decomposition generated significant levels of toxic phosgene from air-polluting quantities of chloroform in poorly ventilated operating rooms that were illuminated by flames. Phosgene is also generated metabolically from chloroform. A clue appeared in the 1950s when subanesthetic traces of inhaled chloroform proved accidentally lethal to strains of male mice spontaneously expressing high levels of chloroform-metabolizing enzymes. Furthermore, in microbial experiments of 1967, the reactive chloroform molecule was inadvertently discovered to selectively inactivate vitamin B12-dependent enzymes. Chloroform can also activate enzymes. As a solvent, it was serendipitously found in 1903 to activate what is now known as plasminogen to plasmin.
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PMID:Noteworthy Chemistry of Chloroform. 2748 Apr 74