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Mechanism of Action of omega-Amino Acids on Plasminogen Activation and Fibrinolysis Induced by Staphylokinase

M. Yu. Levashov1, R. B. Aisina1*, K. B. Gershkovich2, and S. D. Varfolomeyev1

1Chemical Faculty, Lomonosov Moscow State University, 119992 Moscow, Russia; fax: (495) 939-5417; E-mail: arb@enzyme.chem.msu.ru

2Institute of Biochemical Physics, Russian Academy of Sciences, ul. Kosygina 4, 119991 Moscow, Russia; fax: (495) 137-4101; E-mail: gkb@enzyme.chem.msu.ru

* To whom correspondence should be addressed.

Received February 27, 2007; Revision received April 10, 2007
Stimulation of Lys-plasminogen (Lys-Pg) and Glu-plasminogen (Glu-Pg) activation under the action of staphylokinase and Glu-Pg activation under the action of preformed plasmin-staphylokinase activator complex (Pm-STA) by low concentrations and inhibition by high concentrations of omega-amino acids (>90-140 mM) were found. Maximal stimulation of the activation was observed at concentrations of L-lysine, 6-aminohexanoic acid (6-AHA), and trans-(4-aminomethyl)cyclohexanecarboxylic acid 8.0, 2.0, and 0.8 mM, respectively. In contrast, the Lys-Pg activation rate by Pm-STA complex sharply decreased when concentrations of omega-amino acids exceeded the above-mentioned values. It was found that formation of Pm-STA complex from a mixture of equimolar concentrations of staphylokinase and Glu-Pg or Lys-Pg is stimulated by low concentrations (maximal at 10 mM) of 6-AHA. Negligible increase in the specific activities of plasmin and Pm-STA complex was detected at higher concentrations of 6-AHA (to maximal at 70 and 50 mM, respectively). Inhibitory effects of omega-amino acids on the rate of fibrinolysis induced by staphylokinase, Pm-STA complex, and plasmin were compared. It was found that inhibition of staphylokinase-induced fibrinolysis by omega-amino acids includes blocking of the reactions of Pm-STA complex formation, plasminogen activation by this complex, and lysis of fibrin by forming plasmin as a result of displacement of plasminogen and plasmin from the fibrin surface. Thus, the slow stage of Pm-STA complex formation plays an important role in the mechanism of action of omega-amino acids on Glu-Pg activation and fibrinolysis induced by staphylokinase. In addition to alphabeta change of Glu-Pg conformation, stimulation of Pm-STA complex formation leads to increase in Glu-Pg activation rate in the presence of low concentrations of omega-amino acids. Inhibition of Pm-STA complex formation on fibrin surface by omega-amino acids is responsible for appearance of long lag phases on curves of fibrinolysis induced by staphylokinase.
KEY WORDS: staphylokinase, plasmin-staphylokinase complex, plasminogen activation, omega-amino acids, stimulation, fibrinolysis, inhibition, kinetics

DOI: 10.1134/S0006297907070048