Protease Inhibitor

Alpha1 Antitrypsin
is an essential protease
inhibitor in blood plasma. It binds to a wide
range of proteases, such as elastase, trypsin,
chemotrypsin, thrombin, and bacterial proteases.
Its most important physiological effect is
the inhibition of leukocyte elastase, a protease
that breaks down the elastin of the pulmonary
alveolar walls. Deficiency of !1-antitrypsin
leads to increasing destruction of the pulmonary
alveoli, obstructive emphysema of the
lungs, and in newborns, a form of hepatitis.

Alpha1 Antitrypsin

!1-Antitrypsin (1) in humans is a glycoprotein
composed of 394 amino acids and 12% carbohydrate.
It is coded for by a 10.2 kb gene with five
exons on chromosome 14

Antitrypsin deficiency

The uninhibited action of leukocyte elastase on
the elastin of the pulmonary alveoli leads to
chronic obstructive pulmonary emphysema (1).
(Radiograph from N. Konietzko, Essen.) The
most frequent deficiency allele is Pi(Z). The
plasma concentration of !1-AT with genotype
PiZZ (homozygote) is usually about 12–15% of
normal (with the normal allele M). MZ heterozygotes
have 64%, and MS heterozygotes 86%
of MM homozygote activity. !1-Antitrypsin
deficiency in the lung can be corrected by intravenous
administration of !1-antitrypsin.

!1-Antitrypsin: protein, gene, and important mutations

The !1-antitrypsin protein has three oligosaccharide
side chains at positions 46, 83, and
247. The protein is highly polymorphic because
of differences in the amino acid sequence and in
carbohydrate side chains. The reactive site is located
at position 358/359 (methionine/serine).
Clinically, the most important mutations affect
codons 213 (PiZ), 256 (PiP), 264 (PiS), 342 (PiZ),
and 357 (Pi[Pittsburgh]). The gene contains variant
restriction enzyme sites, which can be used
for reliable diagnosis. Today the diagnosis is
often made using the PCR reaction.

Synthesis of !1-antitrypsin

The !1-AT gene is expressed in liver cells (hepatocytes).
The gene product is channeled
through the Golgi apparatus and released from
the cell (secreted). The Z mutation leads to
aggregation of the enzyme in the liver cells,
with too little of it being secreted. The S mutation
leads to premature degradation. About
2–4% of the population in Central and Northern
Europe are MZ heterozygotes.

Reactive center of protease inhibitors

!1-Antitrypsin is one member of a family of
protease inhibitors that show marked homology,
especially at their reactive centers. Oxidizing
substances have an inhibitory effect and
inactivate the molecule. Smokers have a much
more rapid course of !1-AT deficiency disease

Blood Coagulation Factor VIII (Hemophilia A)

Hemophilia was the first major disease recognized
to be genetically determined. The Talmud
refers to its increased occurrence in males in
certain families, corresponding with X-chromosomal
inheritance. Hemophilia A results from
the deficiency of blood coagulation factor VIII;
hemophilia B results from a deficiency of factor
IX. Factor VIII functions as a cofactor in the activation
of factor X to factor Xa during the intermediate
phase of the coagulation cascade.