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Physiology

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Description

Alpha 1-antitrypsin or α1-antitrypsin (A1AT) is a serine protease inhibitor (serpin).[1] It protects tissue from enzymes from inflammatory cells, especially elastase, and is present in human blood at 1.5 - 3.5 gram/liter.

Function

A1AT is a 52 kDa serine protease inhibitor, and in medicine it is considered the most prominent one, 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 area of secondary structure including beta sheets and alpha helices. It is in this area where mutations can lead to polymerisation and accumulation in the liver.

Role in disease

Disorders of the enzyme include alpha 1-antitrypsin deficiency, a hereditary disorder in which lack of alpha 1-antitrypsin leads to uninhibited tissue breakdown during inflammation. This causes pulmonary emphysema and leads to liver cirrhosis in severe cases.[2]

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.

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.

History

The possibility of allelic variants of A1AD leading to disease was first investigated by Axelsson and Laurell in 1965.[3]

References

1. Gettins PG (2002). "Serpin structure, mechanism, and function". Chem Rev 102 (12): 4751-804. PMID 12475206 DOI 10.1021/cr010170+.

2. DeMeo DL, Silverman EK (2004). "Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk". Thorax 59 (3): 259-64. PMID 14985567 DOI 10.1136/thx.2003.006502.

3. Axelsson U, Laurell CB (1965). "Hereditary variants of serum alpha-1-antitrypsin". Am J Hum Genet 17 (6): 466-72. PMID 4158556.

Attribution

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