Generation of active fragments from human zymogens in the bradykinin-generating cascade by extracellular proteases from Vibrio vulnificus and V. parahaemolyticus.
Vibrio vulnificus is an opportunistic human pathogen causing septicemia, and the infection is characterized by formation of the edematous skin lesions on limbs. This pathogenic species secretes a thermolysin-like metalloprotease as a virulence determinant. The metalloprotease was confirmed to activate human factor XII-plasma kallikrein-kinin cascade that results in liberation of bradykinin, a chemical mediator enhancing the vascular permeability, from high-molecular weight kininogen. Namely, the metalloprotease showed to generate active fragments by cleavage of Arg-Ile, Arg-Val or Gly-Leu peptide bond in human zymogens (plasma prekallikrein and factor XII). In spite of induction of the sufficient vascular permeability-enhancing and edema-forming reaction in the guinea pig model, a serine protease from V. parahaemolyticus, a human pathogen causing primarily watery diarrhea, showed far less ability to activate and to cleave the human zymogens. These results in part may explain why only V. vulnificus often causes serious edematous skin damages in humans.
Miyoshi
Shin-ichi
S
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-Naka, Okayama 700-8530, Japan. miyoshi@pharm.okayama-u.ac.jp
Watanabe
Hirofumi
H
Kawase
Tomoka
T
Yamada
Hidenori
H
Shinoda
Sumio
S
D000595:Amino Acid Sequence; D000818:Animals; D001779:Blood Coagulation Factors / Q000378:metabolism*; D001920:Bradykinin / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D005174:Factor XII / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D010447:Peptide Hydrolases / Q000302:isolation & purification / Q000378:metabolism*; D011288:Prekallikrein / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D014736:Vibrio parahaemolyticus / Q000201:enzymology*; D041261:Vibrio vulnificus / Q000201:enzymology*
D001779:Blood Coagulation Factors; D004792:Enzyme Precursors; D005174:Factor XII; D011288:Prekallikrein; D045726:Metalloproteases; D010447:Peptide Hydrolases; D007610:Kallikreins; D012697:Serine Endopeptidases; D001920:Bradykinin