Inhibition of activated protein C by recombinant alpha sub(1)-antitrypsin variants with substitution of arginine or leucine for methionine super(358)

alpha sub(1)-Antitrypsin ( alpha sub(1)-AT) was recently identified as a major physiologic plasma inhibitor of activated protein C. The reaction with activated protein C of recombinant alpha sub(1)-AT containing amino acid substitutions at the reactive center was studied. The substitution of Arg super(358) for Met, as observed in a patient with a severe bleeding disorder with the mutant alpha sub(1)-AT Pittsburgh, increased the association rate constant for activated protein C from 1.1 x 10 super(1) to 4.9 x 10 super(4) M super(-1) s super(-1). The association rate constant of activated protein C with protein C inhibitor, a native plasma serpin that contains Arg super(354) at the reactive site, is 6 x 10 super(3) M super(-1) s super(-1) in the absence of heparin.