Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Much of the tissue damage associated with emphysema and other inflammatory diseases has been attributed to the proteolytic activity of neutrophil elastase, a major component of the azurophil granule. Recently, two additional azurophil granule proteins with NH2-terminal sequence homology to elastase were isolated (Gabay, J. E., Scott, R. W., Campanelli, D., Griffith, J., Wilde, C., Marra, M. N., Seeger, M., and Nathan, C. F. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 5610-5614) and designated azurophil granule protein 7 (AGP7) and azurocidin. Azurocidin and AGP7 represent significant protein components of the azurophil granule, together comprising approximately 15% of the acid-extractable protein as judged by reverse-phase high performance liquid chromatography analysis. AGP7 migrates on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as four distinct glycoforms of molecular mass 28-34 kDa, whereas azurocidin exhibits three predominant bands with molecular mass of 28-30 kDa. Treatment of intact azurophil granules with [3H]diisopropyl fluorophosphate resulted in labeling of elastase, cathepsin G, and AGP7, whereas azurocidin was not labeled. Tryptic mapping of 3H-labeled AGP7 allowed us to identify and sequence the active-site polypeptide that has 70% identity to elastase over 20 residues. The active site peptide of azurocidin was also identified by sequence analysis of tryptic fragments and showed 65% identity to the active site of elastase. Surprisingly, the catalytic serine of azurocidin is replaced by glycine, explaining its inability to label with [3H]diisopropyl fluorophosphate. Thus, we have identified two azurophil proteins closely related to neutrophil elastase, one of which has apparently lost its proteolytic activity due to mutation of the catalytic serine.
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PMID:Characterization of two azurphil granule proteases with active-site homology to neutrophil elastase. 240 77

The granule-associated elastase homologues neutrophil elastase (NE), proteinase 3 (PR3), and azurocidin (AZU) are involved in immune defense reactions of neutrophils and monocytes. Proteinase 3 and NE contribute to the destruction and elimination of microorganisms, cleave elastin and other proteins of connective tissues, and generate chemotactic activities by forming alpha 1-proteinase inhibitor (alpha 1-PI) complexes. Azurocidin is cytotoxic to certain microorganisms and chemotactic to monocytes. All three proteins are produced and packaged into azurophil granules in large quantities during neutrophil development. The genes encoding AZU, PR3, and NE are closely clustered in this sequence within 50 kb of genomic DNA and have the same transcriptional orientation. All three genes show the same exon-intron organization as neutrophil cathepsin G, mast cell chymase 1, and the lymphocyte serine proteases, granzymes A, B, and H. The AZU-PR3-NE gene cluster was mapped to the telomeric region on the short arm of human chromosome 19 (19p13.3), whereas cathepsin G, lymphocyte granzymes B and H, and mast cell chymase 1 are organized as a separate gene cluster on chromosome 14q11.2. Neutrophil-derived serine proteases are widely regarded as pathogenic factors in degenerative and inflammatory diseases with abnormal tissue catabolism. Autoantibodies against PR3 are an obligate feature in the pathogenesis of Wegener's granulomatosis, a systemic autoimmune vasculitis. In addition, PR3 appears to regulate growth and terminal differentiation of the myelomonocyte lineage. Future investigations will clarify whether allelic variations in the AZU-PR3-NE locus predispose patients to increased degradation of elastic fibers, as in pulmonary emphysema, and to the formation of autoantibodies against PR3 in patients with Wegener's granulomatosis.
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PMID:Structure of the azurocidin, proteinase 3, and neutrophil elastase genes. Implications for inflammation and vasculitis. 795 51