Alpha 1-antitrypsin

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Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1
Symbols SERPINA1 ; PI; A1A; A1AT; AAT; MGC23330; MGC9222; PI1; PRO2275
External IDs Template:OMIM5 Template:MGI HomoloGene20103
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Species Human Mouse
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

Alpha 1-Antitrypsin or α1-antitrypsin (A1AT) is a glycoprotein and generally known as serum trypsin inhibitor. The correct name, however, is alpha-1 proteinase inhibitor (A1PI) because it is a serine protease inhibitor (serpin) inhibiting a wide variety of proteases.[1] It protects tissues from enzymes of inflammatory cells, especially elastase, and is present in human blood at 1.5 - 3.5 gram/liter, but the concentration can rise manyfolds upon acute inflammation.[2] In its absence, elastase is free to break down elastin -- which contributes to the elasticity of the lungs -- resulting in respiratory complications such as emphysema leading finally to COPD (chronic obstructive pulmonary disease).


A1AT is a 52 kDa 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 liver cirrhosis).

Role in disease

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.[3]

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.

Differential Diagnosis of Decreased and Increased Alpha-1 Antitrypsin

Alpha-1 Antitrypsin Deficiency

Increased Alpha-1 Antitrypsin


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.

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 inhibitor1-PI).


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 mutant form of A1AT.

Biochemical Properties

A1AT is a single chain glycoprotein consisting of 394 amino acids in the mature form. The three N-linked glycosylations sites are mainly equipped with so-called diantennary N-glycans. However, one particular site shows a considerable amount of heterogeneity since tri- and even tetraantennary N-glycans can be attached to the Asparagine 107 (ExPASy amino acid nomenclature). These glycans carry different amounts of negatively-charged sialic acids, this causes the heterogeneity observed on normal A1AT when analysed by isoelectric focussing. In addition, the fucosylated triantennary N-glycans were shown to have the fucose as part of a so-called Sialyl Lewis X epitope, which could confer this protein particular protein-cell recognition properties. The single cysteine residue of A1AT in position 256 (ExPASy nomenclature) is found to be covalently linked to a free single cysteine by a disulfide bridge.[6]


As protein electrophoresis 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 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.

In blood test results, the electrofocusing results are notated as in PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that patient.

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.

Therapeutic use

Alpha 1-antitrypsin
Clinical data
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Molar mass44324.5 g/mol

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[7]. They are administered intravenously at a dose of 60 ml/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.[8]

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.[9]

See also


  1. Gettins PG (2002). "Serpin structure, mechanism, and function". Chem Rev. 102 (12): 4751–804. PMID 12475206 DOI 10.1021/cr010170+.
  2. Kushner, Mackiewicz A (1993). The acute phase response: an overview. CRC Press. pp. 3–19. Unknown parameter |book= ignored (help)
  3. 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.
  4. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:77 ISBN 1591032016
  5. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:68 ISBN 140510368X
  6. Kolarich D, Weber A, Turecek PL, Schwarz HP, Altmann F (2006). "Comprehensive glyco-proteomic analysis of human alpha1-antitrypsin and its charge isoforms". Proteomics. 6 (11): 3369–80. PMID 16622833 DOI [1].
  7. Alkins SA, O'Malley P (2000). "Should health-care systems pay for replacement therapy in patients with alpha(1)-antitrypsin deficiency? A critical review and cost-effectiveness analysis". Chest. 117 (3): 875–80. PMID 10713018.
  8. Kolarich D, Turecek PL, Weber A, Mitterer A, Graninger M, Matthiessen P, Nicolaes GA, Altmann F, Schwarz HP (2006). "Biochemical, molecular characterization, and glycoproteomic analyses of alpha(1)-proteinase inhibitor products used for replacement therapy". Transfusion. 46 (11): 1959–77. PMID 17076852 DOI [2].
  9. Axelsson U, Laurell CB (1965). "Hereditary variants of serum alpha-1-antitrypsin". Am J Hum Genet. 17 (6): 466–72. PMID 4158556.

Further reading

  • Wu Y, Foreman RC (1991). "The molecular genetics of alpha 1 antitrypsin deficiency". Bioessays. 13 (4): 163–9. doi:10.1002/bies.950130404. PMID 1859394.
  • Kalsheker N (1989). "Alpha 1-antitrypsin: structure, function and molecular biology of the gene". Biosci. Rep. 9 (2): 129–38. PMID 2669992.
  • Crystal RG (1990). "The alpha 1-antitrypsin gene and its deficiency states". Trends Genet. 5 (12): 411–7. PMID 2696185.
  • Carrell RW, Jeppsson JO, Laurell CB; et al. (1982). "Structure and variation of human alpha 1-antitrypsin". Nature. 298 (5872): 329–34. PMID 7045697.
  • Elliott PR, Abrahams JP, Lomas DA (1998). "Wild-type alpha 1-antitrypsin is in the canonical inhibitory conformation". J. Mol. Biol. 275 (3): 419–25. doi:10.1006/jmbi.1997.1458. PMID 9466920.
  • Miyamoto Y, Akaike T, Maeda H (2000). "S-nitrosylated human alpha(1)-protease inhibitor". Biochim. Biophys. Acta. 1477 (1–2): 90–7. PMID 10708851.
  • Coakley RJ, Taggart C, O'Neill S, McElvaney NG (2001). "Alpha1-antitrypsin deficiency: biological answers to clinical questions". Am. J. Med. Sci. 321 (1): 33–41. PMID 11202478.
  • Lomas DA, Lourbakos A, Cumming SA, Belorgey D (2002). "Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia". Biochem. Soc. Trans. 30 (2): 89–92. doi:10.1042/ Check |doi= value (help). PMID 12023831.
  • Kalsheker N, Morley S, Morgan K (2002). "Gene regulation of the serine proteinase inhibitors alpha1-antitrypsin and alpha1-antichymotrypsin". Biochem. Soc. Trans. 30 (2): 93–8. doi:10.1042/ Check |doi= value (help). PMID 12023832.
  • Perlmutter DH (2003). "Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury". J. Clin. Invest. 110 (11): 1579–83. PMID 12464659.
  • Lomas DA, Mahadeva R (2003). "Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy". J. Clin. Invest. 110 (11): 1585–90. PMID 12464660.
  • Lisowska-Myjak B (2005). "AAT as a diagnostic tool". Clin. Chim. Acta. 352 (1–2): 1–13. doi:10.1016/j.cccn.2004.03.012. PMID 15653097.
  • Lomas DA (2005). "Molecular mousetraps, alpha1-antitrypsin deficiency and the serpinopathies". Clinical medicine (London, England). 5 (3): 249–57. PMID 16011217.
  • Rudnick DA, Perlmutter DH (2005). "Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease". Hepatology. 42 (3): 514–21. doi:10.1002/hep.20815. PMID 16044402.
  • Mahr AD, Neogi T, Merkel PA (2006). "Epidemiology of Wegener's granulomatosis: Lessons from descriptive studies and analyses of genetic and environmental risk determinants". Clin. Exp. Rheumatol. 24 (2 Suppl 41): S82–91. PMID 16859601.
  • González-Sagrado M, López-Hernández S, Martín-Gil FJ, et al. (2000). "Alpha1-antitrypsin deficiencies masked by a clinical capillary electrophoresis system (CZE 2000)". Clinical Biochemistry, 33(1):79–80

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