Modulation of plasminogen activation and plasmin activity by methylglyoxalmodification of the zymogen

The effect of methylglyoxal on the plasminogen-plasmin system is studied. T reatment of plasminogen with methylglyoxal at a 20-fold molar excess result s in covalent modification of the molecule as evidenced by the decreased nu mber of NH2 side chains, arginine side chain residues and the new band in t he non-tryptophan dependent fluorescent spectrum. This structural modificat ion is associated with profound functional alterations: the rate of activat ion by streptokinase, tissue-type plasminogen activator, urokinase-type pla sminogen activator and trypsin decreases and the amidolytic activity of the generated plasmin is impaired. Plasmin treatment with methylglyoxal on the other hand does not alter its steady-state kinetic parameters on a peptidy l-anilide synthetic substrate, indicating that modification susceptible sid e chains are sensitive to methylglyoxal only in the zymogen. Our data sugge st that in vivo fibrinolysis could be impaired under pathological condition s, e.g. increased methylglyoxal formation in diabetes mellitus. (C) 2000 El sevier Science B.V. All rights reserved.