Converting Tissue Type Plasminogen Activator into a Zymogen

摘要: In stark contrast to most other members of the chymotrypsin family serine proteases, tissue type plasminogen activator (t-PA) is not synthesized and secreted as a true zymogen. Instead, single-chain t-PA exhibits very significant catalytic activity. Consequently, zymogenicity, or ratio efficiencies mature, two-chain enzyme precursor, only 3-9 for t-PA. Both we others have previously proposed that Lys156 may contribute directly this exceptional property by forming interactions selectively stabilize active conformation enzyme. To test hypothesis created variants in which was replaced tyrosine residue. As predicted, K156Y mutation suppressed activity thereby substantially enhanced enzyme's zymogenicity. addition, however, produced dramatic increase ability discriminate among distinct fibrin co-factors. Compared with wild t-PA, one characterized study, t-PA/R15E,K156Y, possessed response selectivity co-factors, resistance inhibition inhibitor 1, significantly increased The combination these properties, maintenance full presence fibrin, suggest R15E,K156Y mutations extend therapeutic range