Alpha-1 antitrypsin (α1AT) is an efficient inhibitor of the human neutrophil proteases, elastase and cathepsin G. The reactive centre P1 residue (Met358) of α1AT is important in defining the specificity of inhibition; furthermore, oxidation of this residue results in a loss of inhibitor activity. There is evidence that oxidative inactivation of α1AT may be involved in the pathogenesis of pulmonary emphysema associated with cigarette smoking. We have studied the effect of a series of amino acid replacements at the active centre on the inhibition properties of α1AT. The mutant proteins were produced in E. coli following in vitro mutagenesis of the α1AT cDNA. Alpha-1-AT (Ile358), (Ala358) and (Val558) were efficient inhibitors of both neutrophil and pancreatic elastase, but not cathepsin G. Alpha-1-AT (Ala356, Val358) and α1AT (Phe358) were specific for pancreatic elastase and cathepsin G respectively. Alpha-1-AT (Leu358) inhibited both neutrophil elastase and cathepsin G. These data show that, for effective inhibition, a potential cleavage site for the protease must be displayed at the α1AT active centre. In each case, replacement of Met358 led to resistance to oxidative inactivation. Since α1AT (Leu358) inhibits both neutrophil proteases and is resistant to oxidation, this variant may be of increased potential for the therapy of destructive lung disorders.
|Number of pages||12|
|Journal||Revue Francaise de Transfusion et Immuno-Hematologie|
|Publication status||Published - 1 Jan 1986|
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