56
In summary, C1-INH exerts its effects on 4 interconnected
enzyme cascades by forming a covalent bond between
the exposed mobile reactive loop of C1-INH and the active
site of the target protease (Table 15). These interactions
take place on the C-terminal domain, or serpin domain, of
the C1-INH molecule.
It is this inhibition at the early stages of these cascades, as
well as C1-INH’s ability to prevent kallikrein from releasing
bradykinin from HMWK (Figure 27), that makes it possible
for Berinert
®
to control vascular permeability during an
HAE attack.
Enzyme Cascade
C1-INH Target of Protease Inhibition
Estimated Extent of Inhibition by C1-INH
Complement System
C1r
100%
C1s
100%
MASPs
Primary inhibitor
Kallikrein-kinin System
FXIIa (alpha-FXIIa)
90%
FXIIf (beta-FXIIa)
90%
Kallikrein
Primary inhibitor
Coagulation Cascade
Thrombin
Minor role under normal conditions
FXIa
47%
Fibrinolytic System
Plasmin
Usually minor; inhibition increases during HAE attacks
Tissue plasminogen activator
Unknown; inhibition increases during HAE attacks
Table 15 – C1-INH Inhibits Numerous Target Proteases at its Serpin Domain
5,106
