Susceptibility of plasminogen activators to suicide inactivation.
Halomethylated derivatives of dihydrocoumarins are efficient enzyme-activated inhibitors ("suicide" substrates) of plasminogen activators. Kinetic analysis indicate that the one-chain and two-chain forms of the human plasminogen activator are inhibited by 3,4-dihydro-3-benzyl-6-chloromethylcoumarin through a mechanism-based inactivation characterized by the following kinetic parameters (4 degrees C, pH 6.8) : k2 equal to 0.02 s-1 and 0.03 s-1 (for one- and two-chain tissue plasminogen activators, respectively) and Ki equal to 0.16 mM for both forms. Human urokinase and human tissue-type plasminogen activator can be discriminated on the basis of their inhibition by this suicide substrate. The design of a new series of suicide substrates of serine proteases (functionalized cyclopeptides possessing a potential alkylating function closely related to that found in halomethylated derivatives of dihydrocoumarins) is described.
Mor
A
A
Institut Jacques Monod, Université de Paris VII, France.
Reboud-Ravaux
M
M
Mazaleyrat
J P
JP
Wakselman
M
M
D055598:Chemical Phenomena; D002621:Chemistry; D003374:Coumarins / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors*; D015849:Plasminogen Inactivators; D010959:Tissue Plasminogen Activator / Q000032:analysis* / Q000037:antagonists & inhibitors
D003374:Coumarins; D015849:Plasminogen Inactivators; C058018:3,4-dihydro-3-benzyl-6-chloromethylcoumarin; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator