A cyclopeptidic suicide substrate preferentially inactivates urokinase-type plasminogen activator. |
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Authors: | M Reboud-Ravaux A C Vilain N Boggetto J Maillard C Favreau J Xie J P Mazaleyrat M Wakselman |
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Affiliation: | Laboratoire d'Enzymologie Moléculaire et Fonctionnelle, Institut Jacques Monod, Université de Paris, France. |
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Abstract: | c[Arg-aB-(CH2+SCH3 phi)-Gly4] was designed and studied as a mechanism-based inactivator (suicide substrate) for plasminogen activators (u-PA and t-PA) and plasmin. This compound inhibited u-PA and fulfills criteria expected for the involvement of an enzyme-activated inhibitor: first-order and irreversible process, saturation kinetics, protection by substrate. The limiting first-order rate constant kinact and the apparent enzyme-inhibitor dissociation constant KI were 0.021 s-1 and 9 microM, respectively at pH 7.5 and 25 degrees C. The activation of plasminogen by u-PA is compromised after this enzyme has been treated by the reagent. Plasmin and t-PA were inactivated 40- and 2330-fold less efficiently than u-PA, respectively. |
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