Dual effect of synthetic plasmin substrates on plasminogen activation.
The effect of plasmin substrates D-valyl-L-leucyl-lysine-p-nitroanilide (S-2251) and H-D-norleucyl-hexahydrotyrosyl-lysine-p-nitro-anilide (Spectrozyme-PL) on the rate of activation of native human plasminogen in physiological salt solution is studied. Plasminogen activation by two-chain urokinase-type plasminogen activator (urokinase), two-chain tissue-type plasminogen activator (tc-tPA) or trypsin, but not by single chain tPA (sc-tPA) is increased 5- to 10-fold by both substrates, as determined by electrophoretic and spectrophotometric kinetic analysis. The amidolytic activity of sc-tPA, on the other hand, is inhibited by the plasmin substrates in a non-competitive manner (K1 of 6.4 . 10(-4) M for S-2251 and 2.9 . 10(-4) M for Spectrozyme-PL), whereas urokinase and tc-tPA activities are not affected. It is concluded that plasmin substrates containing a lysine residue have a general capacity to enhance plasminogen activation presumably by inducing a conformational change in the native zymogen in a manner similar to 6-aminohexanoate, while the same substrates are inhibitory both on the amidolytic activity of sc-tPA and the activation of native and des1-77-plasminogen by sc-tPA.
Kolev
K
K
Department of Biochemistry II, Semmelweis University of Medicine, Budapest, Hungary.
Owen
W G
WG
Machovich
R
R
D004789:Enzyme Activation; D005341:Fibrinolysin / Q000737:chemistry*; D007700:Kinetics; D009842:Oligopeptides / Q000494:pharmacology; D010958:Plasminogen / Q000737:chemistry; D010960:Plasminogen Activators / Q000494:pharmacology*; D013379:Substrate Specificity; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000494:pharmacology
D009842:Oligopeptides; C018788:valyl-leucyl-lysine 4-nitroanilide; C060237:H-norleucyl-hexahydrotyrosyl-lysine-4-nitroanilide; D010958:Plasminogen; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin