Biology Reference
In-Depth Information
resistant to inhibitors (Owen et al.
1995
). An additional ~2% of NE content is
secreted from the cell in quantum microbursts to transiently overwhelm its inhibitor
(Liou and Campbell
1996
). Additionally, substrate-bound NE is resistant to A1AT
(see below) (Owen and Campbell
1995
).
Serum proteinase inhibition is accomplished by a number of specific proteins
and by the more general inhibitor, Alpha-2 macroglobulin. This massive protein
(~725,000 kDa), which is restricted to the bloodstream due to its size, basically
traps proteinases of numerous classes. Specific inhibition of the serine proteinases
is accomplished by the serpins. The serpins, a superfamily of serine proteinase
inhibitors, function to inhibit the serine elastases both inside and outside of the
bloodstream. Of these, A1AT (or Serpina 1) accounts for most of the antiproteinase
activity found in serum (Davies and Lomas
2008
). The protein is expressed in
humans from two independent alleles of a single gene located on chromosome 14.
Cell-specific expression of A1AT in macrophages and hepatocytes is accomplished
by using different promoters within the same gene (Perlino et al.
1987
). The human
alleles for A1AT are highly polymorphic, with over 70 mutants having been
identified to date (Brantly et al.
1988
). The majority of the population is homozy-
gous for the normal M allele, abbreviated as PiMM. Of the many mutant alleles,
disease states are most commonly associated with the PiZZ genotype, where serum
levels of A1AT are only 10-15% of normal (Yoshida et al.
1976
).
The mature glycoprotein exists as a single polypeptide chain of 395 amino acids
with a molecular weight of approximately 52 kDa (Carrell et al.
1982
). A strained
conformation exists in native A1AT between the Meth
358
and Ser
359
residues that is
relieved when a proteinase cleaves this bond, releasing a C-terminal peptide. The
new pocket formed between the Meth
358
and Ser
359
residues provides an exact fit for
the active site of serine proteinases (Loebermann et al.
1984
). This new A1AT-serine
proteinase complex is rapidly cleared from the circulation, thus the inhibition of a
given proteinase is essentially permanent. The major physiologic function of A1AT
is to inhibit NE. The “antitrypsin” name has been retained for historical purposes,
since trypsin was its first identified substrate. In addition to trypsin and NE, its
substrates include chymotrypsin, plasmin, thrombin, and PR3 (Beatty et al.
1980
).
There are other biologically relevant serine proteinase inhibitors with the capac-
ity to inhibit the serine elastases. Serine leukocyte proteinase inhibitor (SLPI) is
able to inhibit both NE and CG, but not PR3 (Sallenave
2000
). In contrast, elafin is a
small 6-kDa inhibitor of NE and PR3, but likely not CG (Sallenave and Silva
1993
).
These inhibitors are able to inhibit NE when in association with its substrate, a
property not conferred to A1AT.
NE was first implicated in elastic fiber degradation upon the advent of the
proteinase-antiproteinase hypothesis of emphysema pathogenesis. The recognition
that patients with A1AT-deficiency were at increased risk for emphysema, coupled
with the observation that the plant-derived cysteine protease papain could generate
emphysema when instilled into rat lungs (Gross et al.
1965
), gave rise to this theory
that still remains valid nearly 50 years later. Subsequently, investigators have generated
experimental emphysema in rodents using a number of different proteinases includ-
ing pancreatic elastase (Kuhn et al.
1976
), NE (Senior et al.
1977
), and PR3 (Kao
