Thioredoxin-(dithiol-)linked inactivation of elastase

Following inactivation by the alpha-1-antitrypsin (AAT) inhibitor, the protease elastase was reduced by thioredoxin, itself reduced by NADPH and NADP-thioredoxin reductase (NTR). Under these conditions, reduction of enzyme disulfide groups was accompanied by loss of more than 60% of the activity measured following dissociation of the enzyme-inhibitor complex with NaCl. The inhibitor was required (1) to prevent proteolysis of both reduced thioredoxin and NTR and (2) to assess the progress of the reduction reaction. At elevated temperature, elastase was also reduced by dithiols (dithiothreitol and lipoic acid) but not by monothiols (reduced glutathione, beta-mercaptoethanol). When reduced by dithiols under these conditions, the enzyme digested itself. Self-digestion was independent of the antitrypsin inhibitor and was proportional to temperature in the 37-50 degree C range. These findings open the door to a new mode of regulation of elastase and to possible new therapies for treating diseases associated with the enzyme.