title: Proteolytic inactivation of human alpha 1 antitrypsin by human stromelysin.
abstract: alpha 1 Antitrypsin (alpha 1AT) is the main physiological inhibitor of neutrophil elastase, a serine protease which has been implicated in tissue degradation at inflammatory sites. We report here that the connective tissue metalloproteinase, stromelysin, cleaved alpha 1AT (54 kDa), producing fragments of approximately 50 kDa and 4 kDa, as shown by gel electrophoresis. The cleavage of alpha 1AT was accompanied by inactivation of its elastase inhibitory capacity. Isolation of the 4 kDa fragment by reversed-phase HPLC, followed by N-terminal amino acid sequencing, demonstrated that the cleavage of alpha 1AT occurred at the Pro357-Met358 (P2-P1) peptide bond, one peptide bond to the N-terminal side of the inhibitory site. We suggest that stromelysin may potentiate the activity of neutrophil elastase by proteolytically inactivating alpha 1AT.
authors.affiliation: Inflammation Research Group, London Hospital Medical College, UK.
authors.forename: P G
authors.initials: PG
authors.lastname: Winyard
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: K
authors.initials: K
authors.lastname: Chidwick
authors.forename: D R
authors.initials: DR
authors.lastname: Blake
authors.forename: R W
authors.initials: RW
authors.lastname: Carrell
authors.forename: G
authors.initials: G
authors.lastname: Murphy
mesh_terms: D000595:Amino Acid Sequence; D002851:Chromatography, High Pressure Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors; D006801:Humans; D006868:Hydrolysis; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000201:enzymology; D010196:Pancreatic Elastase / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3