50
Berinert
®
is purified and concentrated C1-INH. Research
characterizing the biochemical and physiological roles that
C1-INH plays in health and disease is ongoing, and a com-
plete description of all its functions and their importance
is not yet possible. Similarly, the exact biochemical mecha-
nisms that cause all of the symptoms of HAE are still being
elucidated.
However, much is known about one of the roles played by
C1-INH – that of its function as a serine protease inhibitor.
It is in this role that Berinert
®
is an important regulator at
the early stages of several enzyme cascade systems.
5
To
review, C1-INH is a soluble, single-chain polypeptide with
478 amino acid residues. It has an apparent molecular
weight of approximately 105 kDa, of which carbohydrate
chains comprise 26% to 35%.
The biological functions of C1-INH are conferred by its
configuration and its ability to bind covalently with target
proteases and to interact noncovalently with other sub-
stances. As shown in Figure 25, the C1-INH molecule is
composed of the following:
102
•
C-terminal domain (serpin domain), consisting of
3 beta-sheets and an exposed mobile reactive loop
that binds with target proteases
•
N-terminal domain (nonserpin domain), consisting
of approximately 100 amino acid residues that are
heavily glycosylated with 3 N-linked and 7 O-linked
carbohydrates
•
2 disulfide bridges, which connect the C-terminal
and N-terminal portions of the molecule.
7.0 Berinert
®
Mechanism of Action
Chapter 7 Highlights
•
C1-INH is a member of the serpin family –
a group of plasma proteins that inhibit
proteases by forming covalent bonds
with them.
•
As a serpin, Berinert
®
(C1-INH) is the
primary mediator of the complement
cascade and the kallikrein-kinin system;
it also inhibits the coagulation and fibrinolytic
cascades.
•
These 4 cascades are interconnected,
and during HAE attacks all 4 cascades
are activated.
•
Because Berinert
®
exerts its effects at
critical early stages of these cascades,
it is able to prevent the downstream
formation of bradykinin – a potent
mediator of vascular permeability
produced in the KKS.
•
At its N-terminal domain (nonserpin
domain), C1-INH forms noncovalent
bonds with numerous substrates; the
biochemical mechanisms and clinical
significance of these interactions are
under investigation.
