Identification and characterization of plasma kallikrein-kinin system inhibitors from salivary glands of the blood-sucking insect Triatoma infestans.
Two plasma kallikrein-kinin system inhibitors in the salivary glands of the kissing bug Triatoma infestans, designated triafestin-1 and triafestin-2, have been identified and characterized. Reconstitution experiments showed that triafestin-1 and triafestin-2 inhibit the activation of the kallikrein-kinin system by inhibiting the reciprocal activation of factor XII and prekallikrein, and subsequent release of bradykinin. Binding analyses showed that triafestin-1 and triafestin-2 specifically interact with factor XII and high molecular weight kininogen in a Zn2+-dependent manner, suggesting that they specifically recognize Zn2+-induced conformational changes in factor XII and high molecular weight kininogen. Triafestin-1 and triafestin-2 also inhibit factor XII and high molecular weight kininogen binding to negatively charged surfaces. Furthermore, they interact with both the N-terminus of factor XII and domain D5 of high molecular weight kininogen, which are the binding domains for biological activating surfaces. These results suggest that triafestin-1 and triafestin-2 inhibit activation of the kallikrein-kinin system by interfering with the association of factor XII and high molecular weight kininogen with biological activating surfaces, resulting in the inhibition of bradykinin release in an animal host during insect blood-feeding.
Isawa
Haruhiko
H
Department of Medical Entomology, National Institute of Infectious Diseases, Tokyo, Japan. hisawa@nih.go.jp
Orito
Yuki
Y
Jingushi
Naruhiro
N
Iwanaga
Siroh
S
Morita
Akihiro
A
Chinzei
Yasuo
Y
Yuda
Masao
M
D000595:Amino Acid Sequence; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005174:Factor XII / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D019476:Insect Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D016234:Kallikrein-Kinin System / Q000187:drug effects*; D007700:Kinetics; D007705:Kinins / Q000037:antagonists & inhibitors / Q000097:blood; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010802:Phylogeny; D020842:Plasma Kallikrein / Q000037:antagonists & inhibitors; D011288:Prekallikrein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D012469:Salivary Glands / Q000378:metabolism*; D012471:Salivary Proteins and Peptides / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014224:Triatoma / Q000235:genetics* / Q000378:metabolism; D014914:Whole Blood Coagulation Time; D015032:Zinc / Q000494:pharmacology
D018076:DNA, Complementary; D019476:Insect Proteins; D007705:Kinins; D011994:Recombinant Proteins; D012471:Salivary Proteins and Peptides; C523264:triafestin-1, Triatoma infestans; C523265:triafestin-2, Triatoma infestans; D005174:Factor XII; D011288:Prekallikrein; D020842:Plasma Kallikrein; D015032:Zinc