Biomedical Engineering Reference
In-Depth Information
A. Antiprotease Activity
The crystallographic structure of SLPI reveals a boomerang-like shape with
an N-terminal domain of residues 1-54 and a C-terminal domain composed
of residues 55-107 (45). The antiprotease active site of SLPI has been
located on a loop (residues 67-74) on the C-terminal domain containing
the scissile bond Leu72-Met73. As with AAT, the association rate constant
of SLPI for NE is very high (10
7
M
1
sec
1
) and the rate of dissociation is
low and contains an active site methionine residue (Met73), which is suscep-
tible to oxidative inactivation, rendering it a less effective antiprotease (46).
It has also been shown that the Thr67-Tyr68 bond of the active site loop is
susceptible to cleavage by members of the elastolytic cathepsin family,
cathepsin B, L, and S (25). This is particularly relevant in emphysema where
cleavage products of SLPI have been demonstrated in bronchoalveolar
lavage (BAL) from these individuals. Recent studies strongly suggest that
cathepsins play a putative role in the cleavage of SLPI in emphysema result-
ing in decreased SLPI levels and activity (25). In studies of individuals with
community-acquired pneumonia, SLPI levels were found to be increased in
the infected and uninvolved lobes, in comparison to control lobes. The over-
all anti-NE activity in infected BAL was low consistent with evidence of
SLPI cleavage in infected BAL samples (47). These studies show that while
SLPI levels can increase in certain disease states in response to infection,
activity can be compromised by proteolytic cleavage.
B. Antibacterial Activity
Secretory leukoprotease inhibitor has been shown to have antibacterial
activity towards Escherichia coli and Staphylococcus aureus. The activity
appears to reside in the N-terminal domain of the protein (48). Secretory
leukoprotease inhibitor is one of the most abundant antimicrobial proteins
of the respiratory tract, and, together with lactoferrin and lysozyme, it has
been shown to act synergistically, an effect that is lost upon increasing ionic
strength (49). The SLPI production by uterine epithelial cells, from pre- and
postmenopausal women, differ with greater amounts of SLPI produced by
premenopausal women thus enhancing antibacterial activity (50). Some bac-
teria have evolved ways of inhibiting the antibacterial activity of SLPI and
other respiratory tract antimicrobial proteins. Some virulent strains of
Streptococcus pyogenes produce an extracellular protein called streptococcal
inhibitor of complement (SIC) which is capable of binding to SLPI and inhi-
biting its antibacterial activity against an M1 strain of group A streptococci
(51). Lysozyme is also inhibited by SIC but not lactoferrin. Interestingly,
binding of SIC to SLPI did not affect the antiprotease activity of SLPI, sug-
gesting that SIC may be binding to the N-terminal domain of SLPI but not
the C-terminal domain containing the antiprotease active site.
