Effect of oxidants on proteases of the fibrinolytic system: possible role for methionine residues in the interaction between tissue type plasminogen activator and fibrin.
Evidence has recently been presented that activated macrophages (M phi) express both urinary (u-PA) and tissue type (t-PA) plasminogen activator. Major cell products of M phi and polymorphonuclear neutrophils (PMN) are reactive oxidants of the HOCl/chloramine type. Since PMN and M phi are involved in inflammatory and fibrinolytic processes, we were interested in the interaction of u-PA, t-PA, and plasmin with oxidants of the leukocyte type. The enzymes were treated with chloramine-T, which at pH 8.5 is a selective oxidant for methionine residues. Oxidation by chloramine-T of t-PA abolishes about 40% of both stimulation susceptibility of t-PA by fibrinogen degradation products (FDP) and affinity of t-PA to FDP. However, the plasminogenolytic and amidolytic activity of unstimulated t-PA as well as the plasminogenolytic activity of u-PA and the amidolytic activity of plasmin are not impaired. Identification of the amino acid residues in the t-PA responsible for the interaction with fibrin might be of great importance in order to understand the mechanism of the clot- selectivity of t-PA. The present study gives evidence that fibrin specificity of t-PA partly depends on chloramine oxidizable amino acids, presumably methionine residues. Hence, experimental data on the interaction between t-PA and fibrin, using oxidized and labelled t-PA should be interpreted with caution. It may be suggested that oxidants of the leukocyte type might regulate t-PA activity and selectivity for fibrin.
Stief
T W
TW
Department of Hematology, Univ. Hospital Virgen del Rocío, Seville, Spain.
Martín
E
E
Jimenez
J
J
Digón
J
J
Rodriguez
J M
JM
D002700:Chloramines / Q000494:pharmacology*; D005337:Fibrin / Q000378:metabolism*; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005341:Fibrinolysin / Q000187:drug effects / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D008715:Methionine / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000187:drug effects* / Q000378:metabolism; D014105:Tosyl Compounds
D002700:Chloramines; D005338:Fibrin Fibrinogen Degradation Products; D014105:Tosyl Compounds; C016300:chloramine-T; D005337:Fibrin; D008715:Methionine; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin