Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.7 (peroxidase)
65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polymorphonuclear neutrophilic leukocytes (PMNs) take up opsonized microorganisms into phagosomes that fuse with secretory granules in the PMN cytoplasm to form phagolysosomes. Killing and digestion of microorganisms take place within phagolysosomes. Antimicrobial activities in phagolysosomes are divided into two classes. Oxygen (O2)-dependent mechanisms are expressed when PMNs undergo the "respiratory burst." An NADPH oxidase in the phagolysosome membrane is activated and reduces O2 to superoxide (O2-). O2 reduction is the first step in a series of reactions that produce toxic oxidants. For example, .O2- dismutases to hydrogen peroxide (H2O2), and the azurophil granule enzyme myeloperoxidase catalyzes the oxidation of Cl- by H2O2 to yield hypochlorous acid (HOCl). The reaction of HOCl with ammonia and amines modulates the toxicity of this oxidant. O2-independent antimicrobial mechanisms include the activities of lysosomal proteases, other hydrolytic enzymes, and proteins and peptides that bind to microorganisms and disrupt essential processes or structural components. For example, the bactericidal/permeability-increasing protein, cathepsin G, and the defensins are released into phagolysosomes from the azurophil granules. Proposed mechanisms of action of neutrophil antimicrobial agents, their range of microbial targets, and their possible interactions within phagolysosomes are discussed.
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PMID:Human neutrophil antimicrobial activity. 305 15

The bactericidal activity of the human neutrophil is dependent on a coordinated series of events by which the bacteria become confined to a vacuole. Fusion of the azurophil and specific granules with the phagocytic vacuole results in secretion of BPI, the primary oxygen independent bactericidal protein, and of myeloperoxidase into the phagolysosome. Simultaneously, an electron transport chain, the NADPH oxidase, is activated in the membrane of the phagolysosome, resulting in generation of H2O2, which together with myeloperoxidase and Cl- forms a highly bactericidal agent. Digestion of the killed bacteria is subsequently effectuated by proteases and lipases of the neutrophil granules. The neutrophil thus has several highly efficient bactericidal systems that overlap to a certain degree, thereby giving the neutrophil an overcapacity to kill. This is appreciated in the defence against microorganisms, but is increasingly being recognized as a cause of perturbation of serum protease anti-protease homeostasis that may cause major tissue destruction. The recent achievements in the understanding of neutrophil function will hopefully permit better control to be exerted over this potent cell.
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PMID:Bactericidal mechanisms of the human neutrophil. An integrated biochemical and morphological model. 632 83

After 14 days' bone marrow maturation, neutrophil granulocytes reach the tissues where for 1-2 days they form the army whose phagocytic function was described by llya Metchnikoff in 1882. At that time, Paul Ehrlich was developing his neutrophil secretory theory which had less success until it returned with a vengeance in the last decade. Neutrophils are not only phagocytes. Above all they are cells that secrete bactericidal effectors and regulators (amplifiers and modulators) of the inflammatory focus. More and more sophisticated methods are being used to study phagocytosis, from the point of view both of the mechanism of chemotaxis and its role in inflammation and of the mediators of oxygen-dependent bactericidal action (superoxide anion, oxygenated water, hydroxyl radicals, myeloperoxidase, halogen ions and superoxide dismutase). In addition, the importance of oxygen-independent bactericidal mechanisms has been confirmed by the discovery of proteins such as BPI (Bactericidal Permeability Increasing Protein). Study of neutrophil dysfunction throws light on a number of neutrophil regulatory and effector mechanisms; it also proves useful in explaining the recurrent infections observed in some congenital disorders (chronic granulomatous disease, the "lazy leucocyte syndrome", the Chediak-Higashi syndrome, ichthyrosis , Job's syndrome...) or those associated with transitory neutrophil disorders (measles, severe bacterial infection...). Neutropenia induced by some antibiotics is easily demonstrated, but the interactions between these antibiotics and neutrophils are complex: phagocyte concentration of antibiotic, neutrophil inactivation of antibiotic, effect of antibiotic on microbe-leucocyte interaction such as an alteration in phagocytic and chemotactic response. The neutrophil is the first blood cell to arrive at the inflammatory focus; it is also at the centre of the response, next to the humoral mediators which both act upon it and which it itself secretes.
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PMID:[Neutrophil functions and interactions in the inflammatory reaction]. 673 54

Several LPS-binding proteins have been identified on the surface of human granulocytes (polymorphonuclear leukocyte (PMN)). We describe a plasma-membrane associated ca. 55-kDa LPS-binding protein of human PMN that is indistinguishable from the bactericidal/permeability-increasing protein (BPI). To detect LPS-binding proteins on the cell surface, PMN were biotinylated before detergent solubilization and incubation with LPS-coated beads. Several biotinylated proteins bound to LPS-coated beads but not to uncoated beads and were characterized after elution with detergent by SDS-PAGE and western blotting using streptavidin-horseradish peroxidase. The spectrum of biotinylated proteins binding to and eluting from LPS-coated beads increased as the number of beads incubated with PMN lysate increased. However, at all concentrations of beads a 55-kDa protein was a dominant component of the eluate. Binding of the 55-kDa protein to LPS-coated beads was inhibited by lipid A, and both homologous and heterologous LPS, but not by peptidoglycan. Similar amounts of biotinylated 55-kDa LPS-binding protein were detected on PMN from patients with paroxysmal nocturnal hemoglobinuria who lacked membrane bound CD14, a known ca. 55-kDa plasma membrane-associated LPS-binding protein, indicating that the recovered biotinylated protein is not CD14. Several pieces of evidence, however, do indicate that the 55-kDa surface protein is BPI: 1) flow cytometry of PMN after labeling with rabbit anti-BPI serum and FITC-labeled goat anti-rabbit IgG revealed immunoreactive surface molecules on resting PMN and, in increased amounts, on PMN stimulated with FMLP or TNF; 2) This antiserum specifically and quantitatively inhibited binding of the biotinylated 55-kDa species to LPS-coated beads; 3) both BPI and the 55-kDa protein migrated as a doublet during SDS-PAGE and were both converted to single migrated species after N-glycosidase F treatment; 4) chemical cleavage of the biotinylated protein and native BPI with N-chlorosuccinimide yielded the same fragments. Thus, we have positively identified BPI as a LPS-binding protein on the surface of PMN. The role of this potent antibacterial, endotoxin neutralizing protein on the surface of PMN remains to be established.
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PMID:Human granulocytes express a 55-kDa lipopolysaccharide-binding protein on the cell surface that is identical to the bactericidal/permeability-increasing protein. 767 30

Indirect immunofluorescence (IIF) techniques have shown that ANCA are useful serological markers for some small vessel vasculitides, and ELISA assays, using purified molecules as solid-phase ligand, have helped to identify proteinase 3 (PR3) and myeloperoxidase (MPO) as two of the major ANCA antigens. There remain a substantial number of serum samples, which are positive by IIF, yet recognize neither PR3 nor MPO (double-negative samples). We found, by Western blot analysis of soluble neutrophil granule proteins, that certain of these double-negative samples recognized a 55-kD doublet of which the first eight residues shared N-terminal amino acid sequence homology with BPI, a potent antibiotic towards Gram-negative bacteria. We developed a simple, quick and robust two-step immunobiochemical method to purify BPI. This was then employed to detect anti-BPI autoantibodies by ELISA and Western blot analysis. We tested 100 double-negative samples and 400 consecutive new samples sent for routine ANCA testing in the anti-BPI ELISA. We found that 45 of the 100 double-negative and 44 of the 400 new routine samples recognized BPI. By Western blot analysis 20/20 positive anti-BPI samples blotted the 55-kD protein. Inhibition assays confirmed the specificity of binding. Review of the 89 anti-BPI-positive patients showed a male dominance (M:F ratio 55:34), a mean age of 60.4 years and clinical diagnoses ranging from organ limited vasculitis to widespread systemic vasculitis.
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PMID:Bactericidal/permeability-increasing protein (BPI) is an important antigen for anti-neutrophil cytoplasmic autoantibodies (ANCA) in vasculitis. 781 9

Bovine neutrophils contain several cationic polypeptides which exert potent microbicidal effects in vitro. To better characterize the repertoire of these polypeptides, we have incubated extracts of bovine neutrophils or neutrophil granules at pH 4 or 7 with either a smooth strain of Escherichia coli or a rough one. Only a few polypeptides interacted with the bacterial surface and were subsequently desorbed with 200 mM MgCl2, as revealed by gel electrophoresis and analysis of Western blots (immunoblots) with appropriate antibodies. Two of the main proteins appearing in Coomassie blue-stained gels have molecular masses of 53 and 15 kDa and correspond to the heavy and light chains of myeloperoxidase. Another prevailing protein band with a molecular mass of 31 kDa was purified and shown to be 87% identical to human azurocidin/CAP37 in its 22-amino-acid N-terminal sequence. Proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and blotted to nitrocellulose did not react with an antiserum to human bactericidal/permeability-increasing protein. Conversely, immunoglobulin G against Bac7 or Bac5, two members of the antimicrobial proline- and arginine-rich polypeptide family, recognized in Western blots both the inactive precursor molecules, proBac7 and proBac5, and the mature polypeptides.
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PMID:Characterization of bovine neutrophil antibacterial polypeptides which bind to Escherichia coli. 843 16

We isolated a 27-kD protein using cation exchange chromatography from an acid extract of neutrophil granules. N-terminal amino acid sequence analysis of the first 10 residues showed that this protein is azurocidin, a member of the family of neutral serine proteinase found in the neutrophil, which shares amino acid sequence homology with the three other neutral serine proteinases, elastase, proteinase 3 (PR3) and cathepsin G, but unlike them is without proteolytic activity. To test whether, in addition to these proteases, azurocidin might be a target for the humoral autoimmune responses associated with human vasculitis, 185 indirect immunofluorescence (IIF)-positive ANCA sera, made up of four groups of sera with specificities for PR3 (n=37), myeloperoxidase (MPO; n=50), bactericidal/permeability-increasing protein (BPI; n=41) and sera that recognized none of them (triple negative, n=57), and 46 normal sera were screened for IgG anti-azurocidin antibodies using an ELISA incorporating purified azurocidin. Twenty of the 185 IIF-positive sera and 2/46 normal sera displayed reactivity with azurocidin. Positive sera could blot the 27-kD band by Western blot analysis. Further study of the 20 positive sera revealed that: (i) 10 also had autoreactivity for MPO, of which six additionally recognized lactoferrin; (ii) two had reactivity with BPI; (iii) the remaining eight sera were positive only for azurocidin. All 20 sera were from patients with systemic vasculitis, and four of the six sera with triple reactivity (for azurocidin, MPO and lactoferrin) were from patients with hydralazine-induced vasculitis. We concluded that: (i) azurocidin is a novel ANCA antigen; (ii) anti-azurocidin antibodies from a subgroup of patients might represent the consequence of a drug-induced multi-clone activation.
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PMID:Azurocidin is a novel antigen for anti-neutrophil cytoplasmic autoantibodies (ANCA) in systemic vasculitis. 860 37

The major subtypes of anti-neutrophil cytoplasmic antibodies (ANCA) detected by indirect immunofluorescence assay (IFA) are P-ANCA and C-ANCA. In patients with vasculitis, myeloperoxidase (MPO) is the major P-ANCA antigen and proteinase 3 (PR3) is the major C-ANCA antigen. BPI and azurocidin, which are also called 57-kD cationic antimicrobial protein (CAP 57) and 37-kD cationic antimicrobial protein (CAP 37), respectively, have been proposed as less frequent target antigens for C-ANCA and P-ANCA. In patients with renal disease, we determined the frequency of antibodies against BPI and azurocidin. By IFA on alcohol-fixed neutrophils, monoclonal and polyclonal anti-BPI antibodies produced a C-ANCA pattern, whereas rabbit anti-azurocidin antibody produced a P-ANCA pattern. By ELISA, sera from 229 P-ANCA-positive patients, 99 C-ANCA-positive patients and 48 ANCA-negative (by IFA) patients with renal biopsies were tested for reactivity with recombinant human BPI and purified human azurocidin. Of these sera, 17.5% of P-ANCA, 30.3% of C-ANCA and 20.8% of IFA-ANCA-negative sera were positive for anti-BPI; and 8.3% of P-ANCA, 3.0% of C-ANCA and 8.3% of IFA-ANCA-negative sera were positive for anti-azurocidin. There was no statistical difference in frequency of anti-BPI between pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) and other glomerular disease (OGD), and there was a lower frequency of anti-azurocidin in NCGN samples than in OGD samples. By Western blot, anti-BPI-positive sera reacted with a 57-kD BPI band and anti-azurocidin-positive sera with a 29-kD azurocidin band. In conclusion, there is a low frequency of anti-BPI and anti-azurocidin antibodies in ANCA-positive patient sera; however, this does not correlate with NCGN, which is a marker for ANCA-associated small vessel vasculitis, and a similar positivity is found in IFA-ANCA-negative patients with renal disease. Therefore, serologic detection of anti-BPI and anti-azurocidin is not diagnostically specific in patients with renal disease.
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PMID:Frequency of anti-bactericidal/permeability-increasing protein (BPI) and anti-azurocidin in patients with renal disease. 869 20

Cystic fibrosis (CF), a genetic disorder, is characterized by chronic pulmonary infection/inflammation which leads to respiratory failure. The presence of anti-neutrophil cytoplasmic autoantibodies (ANCA) has previously been observed in the sera of patients with CF. In view of the known relationship of ANCA with primary vasculitis and of their putative pathogenetic role in these disorders, we studied the presence, specificity and isotype of ANCA and their clinical associations in 66 adult CF patients. None of the 66 CF samples had autoantibodies to the major ANCA antigens, proteinase 3 or myeloperoxidase. However, 60/66 (91%) CF samples contained IgG, and 55/66 (83%) IgA, autoantibodies to bactericidal/permeability-increasing protein (BPI), a recently-characterized ANCA specificity. All the IgA anti-BPI-positive samples were also IgG anti-BPI-positive. The autoantibody specificity was confirmed by inhibition assay and immunoblotting of CF sera against a neutrophil granule preparation. Furthermore, in this cross-sectional study, anti-BPI levels were inversely correlated with the observed reductions in FEV1 and FVC (IgA anti-BPI & FEV1: r = -0.508, p < 0.0001), and both IgG and IgA anti-BPI levels were higher in CF patients with secondary vasculitis (n = 6) than in those without (p < 0.05). ANCA with specificity for BPI were present in the majority of CF sera in this study and autoimmune processes may be associated with the development of pulmonary injury in CF.
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PMID:Autoantibodies against bactericidal/permeability-increasing protein in patients with cystic fibrosis. 1227 11

Indirect immunofluorescence (IIF) techniques have shown that anti-neutrophil cytoplasm autoantibodies (ANCA) are useful serological markers for certain small vessel vasculitides and the non-vasculitic inflammatory disorders. ELISA procedures, using purified molecules as solid phase ligands, helped to identify proteinase 3 (PR3) and myeloperoxidase (MPO) as two major ANCA antigens; and recently we characterised bactericidal/permeability-increasing protein (BPI) as another important ANCA antigen. ANCA against these three antigens are associated with different clinical disorders. Therefore purified antigens are needed to determine these different autoantibody specificities in order to help diagnosis and guide treatment. Here we describe a method using Orange-A dye ligand chromatography and cation exchange chromatography for the sequential purification of PR3, MPO and BPI, from the same starting material, an acid extract of normal human neutrophil granules. After separation the three antigens were free of contamination by each other and no traces were found of other known minor ANCA antigens.
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PMID:A comprehensive method to purify three major ANCA antigens: proteinase 3, myeloperoxidase and bactericidal/permeability-increasing protein from human neutrophil granule acid extract. 889 Aug 99


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