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.
Nomenclature
The enzyme is called "antitrypsin" because of its ability to covalently bind and irreversibly inactivate the enzyme trypsin. (Trypsin, a type of peptidase, is a digestive enzyme active in the duodenum and elsewhere.)
The term alpha-1 refers to the enzyme's behaviour 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.
The alpha region can be further divided into two sub-regions, termed "1" and "2". Alpha 1-antitrypsin is the main enzyme of the alpha-globulin 1 region.
Another name used is alpha-1 proteinase inhibitor (α1-PI).
Genetics
The gene is located on the long arm of the fourteenth chromosome (14q32.1).
Over 80 different versions of α1-antitrypsin have been described in various populations. North-Western Europeans are most at risk for carrying a deviant form of A1AT.
Analysis
As proteinelectrophoresis is imprecise, A1AT is analysed by electrofocusing (isoelectric focusing analysis), where the protein is passed along a pH gradient.
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 more proximal or more 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), will have two different bands showing on electrofocusing.
PiZ is caused by a glutamate to lysine mutation on position 342.
PiS is caused by a glutamate to valine mutation on position 264.
Other, rarer forms have been described; in all, there are over 80 variants.
Therapeutic use
Recombinant alpha 1-antitrypsin is not yet commercially available, but is under investigation as a therapeutic modality in congenital deficiency. Therapeutic concentrates are prepared from the blood plasma of blood donors.
Recently, the FDA has approved the use of Prolastin®, a human plasma-derived serum consisting of 80% human alpha 1-antitrypsin. It is the only commercially available intravenous augmented A1AT therapy and can cost up to $100,000 per year. It is administered intravenously at the dose of 60 ml/kg once a week.
Aerosolized augmented A1AT therapy is under study. This involves inhaling purified human A1AT into the lungs and trapping the A1AT into the lower respitory tract. This method proves more successful than intravenous augmented A1AT therapy because intravenous use of A1AT results in only 10%-15% of the A1AT actually reaching the lower respitory tract, whereas 25%-45% of A1AT can reach the lower respitory tract through inhalation[[Citing sources citation needed]].
History
The possibility of allelic variants of A1AD leading to disease was first investigated by Axelsson and Laurell in 1965.
