Mechanism of enhanced kinin release from high molecular weight kininogen by plasma kallikrein after its exposure to plasmin.
When purified high molecular weight kininogen was incubated with streptokinase-activated plasmin and kallikrein, a larger amount of kinin was released than would have been predicted from the effect of either enzyme alone. To determine the mechanism of this enhancement, high molecular weight kininogen was digested sequentially with these enzymes, and the rates of kinin release and sites of cleavage were determined. Conversion of 133 kd native high molecular weight kininogen to two-chain 112 kd or 102 kd derivatives by plasmin more than doubled the rate of kinin release by kallikrein. Conversely, digestion of high molecular weight kininogen by kallikrein and then plasmin did not enhance the rate of kinin release. The kallikrein cleavage points that provided 112 kd and 102 kd two-chain high molecular weight kininogen were after residues 437 (Arg-Lys) and 389 (Arg-Ser), whereas those for plasmin were after 438 (Lys-His) and 389 (Arg-Ser). epsilon-Aminocaproic acid, which competes for lysine residues that are critical to the binding of plasminogen or plasmin to substrates, inhibited the digestion of high molecular weight kininogen by plasmin, which is consistent with the evidence that the 438-439 Lys-His was a primary site of plasmin attack on high molecular weight kininogen. Furthermore, this cleavage was observed when plasminogen activation was induced in normal and in prekallikrein or Hageman factor-deficient plasmas. We suggest that the generation of fibrinolytic activity in blood could result in enhanced kinin release by kallikrein in regions of inflammation as a result of the collaborative actions of plasmin and kallikrein on high molecular weight kininogen.
Kleniewski
J
J
Department of Pediatrics, University of Cincinnati College of Medicine, OH.
Blankenship
D T
DT
Cardin
A D
AD
Donaldson
V
V
D000596:Amino Acids / Q000032:analysis; D015153:Blotting, Western; D001920:Bradykinin / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005341:Fibrinolysin / Q000494:pharmacology*; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D007610:Kallikreins / Q000097:blood* / Q000494:pharmacology*; D007704:Kininogens / Q000737:chemistry / Q000378:metabolism*; D007705:Kinins / Q000032:analysis / Q000378:metabolism*; D008970:Molecular Weight
D000596:Amino Acids; D007704:Kininogens; D007705:Kinins; D007610:Kallikreins; D005341:Fibrinolysin; D001920:Bradykinin