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The kinetics of plasminogen activation by thrombin-cleaved pro- urokinase
and promotion of its activity by fibrin fragment E-2 and by tissue
plasminogen activator
JN Liu and V Gurewich
Vascular Research Laboratory, New England Deaconess Hospital, Harvard
Medical School, Boston, MA 02215.
Thrombin hydrolyzes the Arg156-Phe157 bond in pro-urokinase (pro-UK), two
residues from the activation site, generating a two-chain form (thromb-UK)
believed to have little activity and that is resistant to plasmin
activation. The kinetic constants for thromb-UK against synthetic substrate
(S2444) were found to be essentially identical to pro-UK. Against native
plasminogen, thromb-UK had a lower Michaelis constant (KM) and a higher
(2-fold) catalytic efficiency. However, this difference with pro-UK was
nullified by carboxypeptidase B (CpB) treatment of thromb-UK to remove the
C-terminal arginine on the A- chain. Plasminogen activation by thromb-UK
was substantially promoted by fibrin fragment E-2 but not by other fibrin
derivatives, a phenomenon previously observed with pro-UK. Similarly, clot
lysis by thromb-UK was promoted by tissue plasminogen activator because
their combined effect was synergistic. Fibrinogenolysis in plasma occurred
at 80-fold the concentration of thromb-UK as pro-UK, reflecting the 90-
fold greater plasmin resistance of thromb-UK. Addition of a CpB inhibitor
to the plasma enhanced fibrinogenolysis by thromb-UK and pro- UK by
approximately 16%, consistent with the promotion of both forms by certain
C-terminal lysines. In conclusion, CpB-thromb-UK corresponds functionally
to a plasmin resistant form of pro-UK, indicating that the catalytic site
of the single-chain pro-UK is unaffected by thrombin cleavage. The effect
of CpB indicates that the C-terminal Arg of thromb- UK slightly enhances
its affinity for plasminogen. Thromb-UK has potential
plasminogen-activating activity at surfaces where C-terminal lysines,
functionally comparable to fragment E-2, are found.
Volume 81,
Issue 4,
pp. 980-987,
02/15/1993
Copyright © 1993 by The American Society of Hematology
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