The present study indicates that the imminent change of tar yields in the European Union to comply with an upper limit of 12 mg/cigarette will not increase (and may somewhat decrease) the incidence of myocardial infarction, unless they indirectly help perpetuate tobacco use. Even low tar cigarettes still greatly increase rates of myocardial infarction, however, especially among people in their 30s, 40s, and 50s, and far more risk is avoided by not smoking than by changing from one type of cigarette to another.

Streptokinase reacts very rapidly with human plasmin (rate constant 5.4 × 107 M−1 s−1) forming a 1:1 stoichiometric complex which has a dissociation constant of 5 × 10−11 M. This plasmin‐streptokinase complex is 105 times less reactive towards α2‐antiplasmin than plasmin, the inhibition rate constant being 1.4 × 102 M−1 s−1. The loss of reactivity of the streptokinase‐plasmin complex towards α2‐antiplasmin is independent of the lysine binding sites in plasmin since low‐Mr plasmin, which lacks these sites, and plasmin in which the sites have been blocked by 6‐amino‐hexanoic acid, are both equally unreactive towards α2‐antiplasmin on reaction with streptokinase. The plasmin‐streptokinase complex binds to Sepharose‐lysine and Sepharose‐fibrin monomer in the same fashion as free plasmin, showing that the lysine binding sites are fully exposed in the complex. Bovine plasmin is rapidly inhibited by human α2‐antiplasmin (k1= 1.6 × 106 M−1 s−1) and similarly loses reactivity towards the inhibitor on complex formation with streptokinase (50% binding at 0.4 μM streptokinase).

No abstract

Human Glu-plasminogen adopts at least three conformations that provide a means for regulating the specificity of its activation in vivo. It has been proposed previously that the closed (alpha) conformation of human Glu-plasminogen is maintained through physical interaction of the kringle 5 domain and a lysine residue within the N-terminal peptide (NTP). To examine this hypothesis, site-directed mutagenesis was used to generate variant proteins containing substitutions either for aspartic acid residues within the anionic centre of the kringle 5 domain or for conserved lysine residues within the NTP. Size-exclusion HPLC and rates of plasminogen activation by urokinase-type plasminogen activator were used to determine the conformational states of these variants. Variants with substitutions within the kringle 5 lysine-binding site demonstrated extended conformations, as did variants with alanine substitutions for Lys50 and Lys62. In contrast, molecules in which NTP residues Lys20 or Lys33 were replaced were shown to adopt closed conformations. We conclude that the lysine-binding site of kringle 5 is involved in maintaining the closed conformation of human Glu-plasminogen via an interaction with the NTP, probably through Lys50 and/or Lys62. These conclusions advance the current model for the initial stages of fibrinolysis during which fibrin is thought to compete with the NTP for the kringle 5 lysine-binding site.