582
chapter 25
RNA and Protein Synthesis
S - v a r ia n t Z - v a r ia n t
« , -A n titry p sin P itts b u rg h .
A n tie la s ta s e a ctiv ity
s w itc h e d to a n tith ro m b in
activ ity .
F I G U R E 2 5 - 1 7
Schematic representation of the amino acid sequence of
a
i -antitrypsin (PiMM) and some of its variants. The amino acid
residues shown are not drawn to scale; CHO represents the oligosaccharide units.
increase in response to trauma and inflammatory stimulus.
Thus, it is known as an acute-phase reactant,
a
; - AT func-
tions by forming a tight complex with the active site of
the target enzyme that inhibits its proteolytic activity. The
enzyme-inhibitor complexes are rapidly cleared by the
reticuloendothelial cells. Thus, oq-AT is a suicide pro-
tein. Many genetic variants of
a \
-AT have been identified
by isoelectric focusing. The oq-AT gene is on chromo-
some 14, is 10.2 kb long, and contains four introns. The
phenotype is based on a codominant pattern with both al-
leles expressed equally. Variants are classified by a system
known as
Pi (protease inhibitor).
The most common form
is PiMM (carried by 95% of the U.S. population). Most
polymorphism observed in
a \
-AT are due to single-amino-
acid substitutions.
oq-AT is a broad-spectrum serine proteinase inhibitor
(Chapter
6
). Its principal action is to inhibit leukocyte
(neutrophil) elastase. This function appears to be most
important in maintaining the integrity of the elastic fibers
for the elastic recoil of normal lung tissue. Recall that elas-
tic fibers contain an amorphous core of elastin surrounded
by an envelope of microfibrils (Chapter 16). The target
substrate for neutrophil elastases is elastin. The turnover
rate of mature elastin is extremely low, and if it is de-
stroyed, replacement is severely limited. Thus, the risk of
development of a lung disease (
emphysema
) characterized
by dilatation of air spaces distal to the terminal bronchi-
ole and destruction of bronchiole walls is high in oq-AT
deficiency.
A human phenotype in which a severe deficiency of
a i-AT (10-15% of normal serum concentration) has been
observed is designated PiZ. The risk of development of
emphysema in PiZZ (homozygotic ZZ individuals) is 20
times that in PiMM (a normal genotype). In addition,
cigarette smoking by PiZ individuals accelerates devel-
opment of destructive lung disease for several reasons.
1. The levels of
a
i -AT are very low, and smoking causes
an increase in elastolytic load owing to change in the
phagocytic population.
2. A reduction of the proteinase inhibitory activity is due
to oxidation of the reactive methionine residue of the
active center by the cigarette smoke as well as by
oxygen radicals produced by leukocytes and
macrophages. Emphysema is a common disease, and
its most common cause is cigarette smoking. Only
1-2% of cases are due to genetic deficiency of o';-AT.
The substitution of a lysine for a glutamic acid at posi-
tion 342 leads to the deficiency of
a \
-AT in PiZ individuals
(Figure 25-17). This substitution of a basic for an acidic
amino acid is consistent with a base change of cytosine to
thymine in DNA. The amino acid change prevents normal
processing of oligosaccharide side chains of the protein
and therefore its secretion. As a result, Z-a,-AT accumu-
lates in hepatocytes. An association of hepatic disease with
severe a i-AT deficiency has been observed; however, the
relationship is not understood. The sequestered
a \
-AT may
cause damage to hepatocytes or render them more suscep-
tible to injury, toxins, or viruses. Liver transplantation has
been attempted with limited success in patients with hepa-
tocellular failure. The therapy for destructive lung disease
is administration of an anabolic steroid (danazol), which
increases the serum levels of a [-AT by about 40%, or
direct replacement of «[-AT by transfusion.
Another structural variant of
a
i -AT that has been stud-
ied in detail is S-apAT (PiSS). This protein differs from
M-a i -AT at position 264, where a glutamic acid residue
is substituted by valine (Figure 25-17). The S-oq-AT un-
dergoes normal addition of oligosaccharides, and the pro-
tein is secreted into the blood. Affected individuals have
sufficiently high levels of S-oq-AT to protect against neu-
trophil elastase and so are not at higher risk for developing
