Antibiotic A10255 (Thioplabin) Enhances Fibrin Binding and Activation of Plasminogen

Abstract

Three thiopeptide metabolites that enhance fibrin binding of plasminogen were isolated from a culture of Streptomyces sp. R1401. A combination of spectroscopic analyses revealed that these compounds were identical with the antibiotic A10255B, E and G. These agents enhanced fibrin binding of plasminogen and plasminogen/urokinase-mediated fibirinolysis at concentrations of 5-20μM. A10255B reversibily increased urokinase-catalyzed activation of plasminogen by lowering K_m, while the agent did not enhance urokinase activity when substrates other than plasminogen were used, indicating that the agent affects plasminogen to increase its affinity to urokinase. A smaller but significant increase in activation was also observed when conformationally relaxed plasminogen derivatives such as Lys-plasminogen and mini-plasminogen were used. Two related thiopeptide antibiotics with a C-terminal amide had no effect on plasminogen activation, suggesting a role of the terminal carboxyl of the A10255 molecule in activity.