A1AT is a 52 kDa serpin (serine protease inhibitor), and in medicine it is considered the most prominent serpin, given the fact that the words α1-antitrypsin and protease inhibitor (Pi) are often used interchangeably.
Most serpins inactivate enzymes by binding to them covalently, requiring very high levels to perform their function. In the acute phase reaction, a further elevation is required to "limit" the damage caused by activated neutrophil granulocytes and their enzyme elastase, which breaks down the connective tissue fiber elastin.
Like all serine protease inhibitors, A1AT has a characteristic secondary structure of beta sheets and alpha helices. Mutations in these areas can lead to non-functional proteins which can polymerise and accumulate in the liver (infantile hepatic cirrhosis).
Disorders of the enzyme include alpha 1-antitrypsin deficiency, a hereditary disorder in which lack of alpha 1-antitrypsin leads to a chronic uninhibited tissue breakdown. This causes the subsequent degradation especially of lung tissue and to the manifestation of pulmonary emphysema. Because A1AT is created in the liver, certain mutations in the DNA code for the enzyme can cause misfolding and impaired secretion of the enzyme, which can lead to liver cirrhosis.
A remarkable form of Pi, termed PiPittsburgh, functions as an antithrombin (a related serpin), due to a mutation (Met358Arg). One patient with this abnormality has been described; he died of a lethal bleeding diathesis. This disorder proves the point that the serine protease inhibitors have a closely related structure.
The protein was called "antitrypsin" because of its ability to covalently bind and irreversibly inactivate the enzyme trypsin in vitro. Trypsin, a type of peptidase, is a digestive enzyme active in the duodenum and elsewhere.
The term alpha-1 refers to the enzyme's behavior on protein electrophoresis. On electrophoresis, the protein component of the blood is separated by electric current. There are several "clusters", the first being albumin, the second being the alpha, the third beta and the fourth gamma (immunoglobulins). The non-albumin proteins are referred to as globulins.
Another name used is alpha-1 proteinase inhibitor (α1-PI).
Over 80 different versions of α1-antitrypsin have been described in various populations. North-Western Europeans are most at risk for carrying a mutant form of A1AT.
Normal A1AT is termed "M", as it is neutral and does not run very far. Other variants are less functional, and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on electrofocusing can signify the presence of alpha 1-antitrypsin deficiency.
As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although heterozygote with one null mutant that abolishes expression of the gene will only show one band.
Alpha 1-antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are thus targeted for destruction in the proteasome, while others have a tendency to polymerise, being retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:
Other rarer forms have been described; in all there are over 80 variants.
Recombinant alpha 1-antitrypsin is not yet commercially available, but is under investigation as a therapy for alpha 1-antitrypsin deficiency. Therapeutic concentrates are prepared from the blood plasma of blood donors.
The FDA has approved the use of three alpha 1-antitrypsin products derived from a human plasma: Prolastin, Zemaira and Aralast. These products for intravenous augmention A1AT therapy can cost up to $100,000 per year per patient. They are administered intravenously at a dose of 60 mg/kg once a week.
A recent study analyzed and compared the three FDA approved products in terms of their primary structure and glycosylation. All three products showed minor differences compared to the normal human plasma A1AT and are introduced during the specific purifications procedures. However, these detected differences are not believed to have any negative implications to the patients.
Aerosolized augmented A1AT therapy is under study. This involves inhaling purified human A1AT into the lungs and trapping the A1AT into the lower respiratory tract. This method proves more successful than intravenous augmented A1AT therapy because intravenous use of A1AT results in only 10%-15% of the A1AT reaching the lower respiratory tract, whereas 25%-45% of A1AT can reach the lower respiratory tract through inhalation.
The possibility of allelic variants of A1AT leading to disease was first investigated by Axelsson and Laurell in 1965.
Genetic predisposition to chronic obstructive pulmonary disease: advances in ¿^sub 1^-antitrypsin deficiency and the serpinopathies
Oct 01, 2007; Alpha^sub 1^-Antitrypsin deficiency is the only widely accepted genetic factor that predisposes smokers to chronic...
Alpha-1 antitrypsin and serum albumin levels in tear fluid of healthy subjects and in persons with conjunctival diseases.(Original Article)(Clinical report)
Jan 01, 1988; Byline: D. Sen, G. Sarin, M. Mathur Alpha-1 Antitrypsin and serum albumin levels were measured in the tear fluids in 81...