Recombinant alpha 1-antitrypsin Pittsburgh (Met 358----Arg) is a potent inhibitor of plasma kallikrein and activated factor XII fragment.
In normal plasma, the serine protease inhibitor alpha 1-antitrypsin (alpha 1-AT) plays little or no role in the control of plasma kallikrein or activated Factor XII fragment (Factor XIIf), this function being performed by Cl-inhibitor. Recently, an alpha 1-AT variant was described with a Met----Arg mutation at the reactive center P1 residue (position 358) which altered the specificity of inhibition from the Met- or Val-specific protease neutrophil elastase to thrombin, an Arg-specific protease. We have now examined the inhibition of plasma kallikrein and Factor XIIf, both Arg-specific enzymes, with recombinant alpha 1-AT(Met358----Arg) produced by an Escherichia coli strain carrying a mutated human alpha 1-AT gene. The engineered protein was a very efficient inhibitor of both enzymes. It was more effective than Cl-inhibitor by a factor of 4.1 for kallikrein and 11.5 for Factor XIIf. These results suggest that recombinant alpha 1-AT(Met358----Arg) has therapeutic potential for disease states where activation of the plasma kinin-forming system is observed, for example in hereditary angioedema or septic shock.
D005174:Factor XII / Q000037:antagonists & inhibitors*; D015956:Factor XIIa; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008970:Molecular Weight; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
D010446:Peptide Fragments; D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin; C038915:alpha 1-antitrypsin Pittsburgh; D005174:Factor XII; D007610:Kallikreins; D015956:Factor XIIa