Alpha 1-antitrypsin

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.cite journal | author=Gettins PG | title=Serpin structure, mechanism, and function | journal=Chem Rev | year=2002 | pages=4751–804 | volume=102 | issue=12 | pmid=12475206 DOI [http://dx.doi.org/10.1021/cr010170+ 10.1021/cr010170+] | doi=10.1021/cr010170 | doi_brokendate=2008-06-21 ] 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.cite book | author=Kushner, Mackiewicz A | title=The acute phase response: an overview. | book= Acute-phase glycoproteins: molecular biology, biochemistry and clinical applications | publisher=CRC Press | year=1993 | pages=3-19] 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).

Function

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).

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.cite journal | author=DeMeo DL, Silverman EK | title=Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk | journal=Thorax | year=2004 | pages=259–64 | volume=59 | issue=3 | pmid=14985567 DOI [http://dx.doi.org/10.1136/thx.2003.006502 10.1136/thx.2003.006502] | doi=10.1136/thx.2003.006502] 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 "Pi"Pittsburgh, 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 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 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 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.cite journal | author=Kolarich D, Weber A, Turecek PL, Schwarz HP, Altmann F | title= Comprehensive glyco-proteomic analysis of human alpha1-antitrypsin and its charge isoforms | journal=Proteomics | year=2006 | pages=3369–80 | volume=6 | issue=11 | pmid=16622833 DOI [http://dx.doi.org/10.1002/pmic.200500751] | doi=10.1002/pmic.200500751]

Analysis

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 "Pi"MM, 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:

* PiMM: 100% (normal)
* PiMS: 80% of normal serum level of A1AT
* PiSS: 60% of normal serum level of A1AT
* PiMZ: 60% of normal serum level of A1AT
* PiSZ: 40% of normal serum level of A1AT
* PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)

* PiZ is caused by a glutamate to lysine mutation at position 342
* PiS is caused by a glutamate to valine mutation at position 264Other rarer forms have been described; in all there are over 80 variants.

Therapeutic use

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IUPAC_name = Alpha-1-proteinase inhibitor


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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 patientcite journal | author=Alkins SA, O'Malley P | title=Should health-care systems pay for replacement therapy in patients with alpha(1)-antitrypsin deficiency? A critical review and cost-effectiveness analysis | journal=Chest | year=2000 | pages=875–80 | volume=117 | issue=3 | pmid=10713018 | doi=10.1378/chest.117.3.875] . 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.cite journal | author=Kolarich D, Turecek PL, Weber A, Mitterer A, Graninger M, Matthiessen P, Nicolaes GA, Altmann F, Schwarz HP | title= Biochemical, molecular characterization, and glycoproteomic analyses of alpha(1)-proteinase inhibitor products used for replacement therapy | journal=Transfusion | year=2006 | pages=1959–77 | volume=46 | issue=11 | pmid=17076852 DOI [http://dx.doi.org/10.1111/j.1537-2995.2006.01004.x] | doi=10.1111/j.1537-2995.2006.01004.x]

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 inhalationFact|date=February 2007.

History

The possibility of allelic variants of A1AT leading to disease was first investigated by Axelsson and Laurell in 1965.cite journal | author=Axelsson U, Laurell CB | title=Hereditary variants of serum alpha-1-antitrypsin | journal=Am J Hum Genet | year=1965 | pages=466–72 | volume=17 | issue=6 | pmid=4158556]

See also

* Trypsin inhibitor

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Wu Y, Foreman RC |title=The molecular genetics of alpha 1 antitrypsin deficiency |journal=Bioessays |volume=13 |issue= 4 |pages= 163–9 |year= 1991 |pmid= 1859394 |doi= 10.1002/bies.950130404
*cite journal | author=Kalsheker N |title=Alpha 1-antitrypsin: structure, function and molecular biology of the gene |journal=Biosci. Rep. |volume=9 |issue= 2 |pages= 129–38 |year= 1989 |pmid= 2669992| doi=10.1007/BF01115992
*cite journal | author=Crystal RG |title=The alpha 1-antitrypsin gene and its deficiency states |journal=Trends Genet. |volume=5 |issue= 12 |pages= 411–7 |year= 1990 |pmid= 2696185 |doi=
*cite journal | author=Carrell RW, Jeppsson JO, Laurell CB, "et al." |title=Structure and variation of human alpha 1-antitrypsin |journal=Nature |volume=298 |issue= 5872 |pages= 329–34 |year= 1982 |pmid= 7045697| doi=10.1038/298329a0
*cite journal | author=Elliott PR, Abrahams JP, Lomas DA |title=Wild-type alpha 1-antitrypsin is in the canonical inhibitory conformation |journal=J. Mol. Biol. |volume=275 |issue= 3 |pages= 419–25 |year= 1998 |pmid= 9466920 |doi= 10.1006/jmbi.1997.1458
*cite journal | author=Miyamoto Y, Akaike T, Maeda H |title=S-nitrosylated human alpha(1)-protease inhibitor |journal=Biochim. Biophys. Acta |volume=1477 |issue= 1-2 |pages= 90–7 |year= 2000 |pmid= 10708851 |doi=
*cite journal | author=Coakley RJ, Taggart C, O'Neill S, McElvaney NG |title=Alpha1-antitrypsin deficiency: biological answers to clinical questions |journal=Am. J. Med. Sci. |volume=321 |issue= 1 |pages= 33–41 |year= 2001 |pmid= 11202478 |doi=
*cite journal | author=Lomas DA, Lourbakos A, Cumming SA, Belorgey D |title=Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia |journal=Biochem. Soc. Trans. |volume=30 |issue= 2 |pages= 89–92 |year= 2002 |pmid= 12023831 |doi= 10.1042/ |doi_brokendate=2008-06-21
*cite journal | author=Kalsheker N, Morley S, Morgan K |title=Gene regulation of the serine proteinase inhibitors alpha1-antitrypsin and alpha1-antichymotrypsin |journal=Biochem. Soc. Trans. |volume=30 |issue= 2 |pages= 93–8 |year= 2002 |pmid= 12023832 |doi= 10.1042/ |doi_brokendate=2008-06-21
*cite journal | author=Perlmutter DH |title=Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury |journal=J. Clin. Invest. |volume=110 |issue= 11 |pages= 1579–83 |year= 2003 |pmid= 12464659 |doi=
*cite journal | author=Lomas DA, Mahadeva R |title=Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy |journal=J. Clin. Invest. |volume=110 |issue= 11 |pages= 1585–90 |year= 2003 |pmid= 12464660 |doi=
*cite journal | author=Lisowska-Myjak B |title=AAT as a diagnostic tool |journal=Clin. Chim. Acta |volume=352 |issue= 1-2 |pages= 1–13 |year= 2005 |pmid= 15653097 |doi= 10.1016/j.cccn.2004.03.012
*cite journal | author=Lomas DA |title=Molecular mousetraps, alpha1-antitrypsin deficiency and the serpinopathies |journal=Clinical medicine (London, England) |volume=5 |issue= 3 |pages= 249–57 |year= 2005 |pmid= 16011217 |doi=
*cite journal | author=Rudnick DA, Perlmutter DH |title=Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease |journal=Hepatology |volume=42 |issue= 3 |pages= 514–21 |year= 2005 |pmid= 16044402 |doi= 10.1002/hep.20815
*cite journal | author=Mahr AD, Neogi T, Merkel PA |title=Epidemiology of Wegener's granulomatosis: Lessons from descriptive studies and analyses of genetic and environmental risk determinants |journal=Clin. Exp. Rheumatol. |volume=24 |issue= 2 Suppl 41 |pages= S82–91 |year= 2006 |pmid= 16859601 |doi=

*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 refend

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