Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0519030 (Klebsiella)
 21,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bac5 and Bac7, antibiotics of the bactenecin (proline/arginine-rich peptide) family, are stored as proforms in the large granules of bovine neutrophils [Zanetti, M., Litteri, L., Gennaro, R., Horstmann, H. and Romeo, D. (1990) J. Cell Biol. 111, 1363-1371]. These proforms have been purified to homogeneity from granule extracts by immunoaffinity and reverse-phase chromatography. While mature bactenecins efficiently kill Escherichia coli, Klebsiella pneumoniae and Salmonella typhimurium with minimal inhibitory concentrations of 6-12 micrograms/ml, proBac5 and proBac7 do not affect the growth of the same microorganisms, even at 500 micrograms/ml. Previous investigations have suggested that the conversion of probactenecins into mature antimicrobial peptides is catalyzed by a neutral serine protease stored in the azurophil granules. Purified proBac5 and proBac7 were thus treated with elastase, cathepsin G or proteinase 3, which constitute the pool of neutral serine proteases of the azurophils, and the reaction products were identified by Western blot analysis, mass spectrometry, and N-terminal sequence analysis. Of the three proteases, only elastase is able to catalyze the stepwise cleavage of probactenecins into the corresponding mature peptides, which have the same mass, N-terminal sequence and antibiotic activity of authentic Bac5 and Bac7. These results point to the importance of cooperation between azurophils and large granules in mounting a defense reaction.
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PMID:Proteolytic cleavage by neutrophil elastase converts inactive storage proforms to antibacterial bactenecins. 142 66

Streptococcus pneumoniae contains an inhibitor of human neutrophil elastase. The agent does not inhibit other proteases, including neutrophil cathepsin G and pancreatic elastase. It is active in the presence of insoluble elastin as well as synthetic elastase substrates. The inhibitor is present in the pneumococcal cell membrane. [125I]elastase binding studies and inhibition experiments with intact bacterial autoplasts suggest that this agent has its elastase-binding site(s) exposed on the outside of the bacterial cell membrane. Native and randomized membrane vesicles also show equal inhibitory activity. Active inhibitor can be solubilized from pneumococcal membranes by treatment with a dipolar ionic detergent and can then be reconstituted, in active form, within artificial liposomes. Complex formation between the neutrophil elastase inhibitor and neutrophil elastase may involve noncovalent associations. Although elastase containing a covalently bound substrate analog no longer binds the pneumococcal inhibitor, the present study shows that complex formation is nevertheless independent of neutrophil elastase catalytic activity. Specific inhibitor activity and inhibitor release during bile salt-stimulated autolysis are greater in a nonnecrotizing pneumococcal strain (type I) than they are in a necrotizing strain (type III) or in Klebsiella pneumoniae. These results may help explain the frequent resolution of some pneumococcal pneumonias, despite the presence in the early pneumonic exudate of many neutrophils containing an elastolytic protease capable of injuring lung connective tissue.
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PMID:Subcellular localization and further characterization of a new elastase inhibitor from pneumococci. 384 90

Neutrophil elastase (NE) is a potent serine proteinase whose expression is limited to a narrow window during myeloid development. In neutrophils, NE is stored in azurophil granules along with other serine proteinases (cathepsin G, proteinase 3 and azurocidin) at concentrations exceeding 5 mM. As a result of its capacity to efficiently degrade extracellular matrix, NE has been implicated in a variety of destructive diseases. Indeed, while much interest has focused on the pathologic effects of this enzyme, little is known regarding its normal physiologic function(s). Because previous in vitro data have shown that NE exhibits antibacterial activity, we investigated the role of NE in host defense against bacteria. Generating strains of mice deficient in NE (NE-/-) by targeted mutagenesis, we show that NE-/- mice are more susceptible than their normal littermates to sepsis and death following intraperitoneal infection with Gram negative (Klebsiella pneumoniae and Escherichia coli) but not Gram positive (Staphylococcus aureus) bacteria. Our data indicate that neutrophils migrate normally to sites of infection in the absence of NE, but that NE is required for maximal intracellular killing of Gram negative bacteria by neutrophils.
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PMID:Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. 958 38

Cathepsin G is a neutral serine protease that is highly expressed at the promyelocyte stage of myeloid development. We have developed a homologous recombination strategy to create a loss-of-function mutation for murine cathepsin G. Bone marrow derived from mice homozygous for this mutation had no detectable cathepsin G protein or activity, indicating that no other protease in bone marrow cells has the same specificity. Hematopoiesis in cathepsin G-/- mice is normal, and the mice have no overt abnormalities in blood clotting. Neutrophils derived from cathepsin G-/- mice have normal morphology and azurophil granule composition; these neutrophils also display normal phagocytosis and superoxide production and have normal chemotactic responses to C5a, fMLP, and interleukin-8. Although cathepsin G has previously shown to have broad spectrum antibiotic properties, challenges of mice with Staphylococcus aureus, Klebsiella pneumoniae, or Escherichia coli yielded survivals that were not different from those of wild-type animals. In sum, cathepsin G-/- neutrophils have no obvious defects in function; either cathepsin G is not required for any of these normal neutrophil functions or related azurophil granule proteases with different specificities (ie, neutrophil elastase, proteinase 3, azurocidin, and/or others) can substitute for it in vivo.
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PMID:Normal neutrophil function in cathepsin G-deficient mice. 1059 73