|Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1|
Crystal structure of serpin A1 (red) in an inhibitory complex with pancreatic elastase (blue). Rendered from PDB 2D26.
|Symbols||; A1A; A1AT; AAT; PI; PI1; PRO2275; alpha1AT|
|RNA expression pattern|
Alpha-1 Antitrypsin or α1-antitrypsin (A1AT) is a protease inhibitor belonging to the serpin superfamily. It is generally known as serum trypsin inhibitor. Alpha 1-antitrypsin is also referred to as alpha-1 proteinase inhibitor (A1PI) because it inhibits a wide variety of proteases. It protects tissues from enzymes of inflammatory cells, especially neutrophil elastase, and has a reference range in blood of 1.5 - 3.5 gram/liter (in US the reference range is generally expressed as mg/dL or micromoles), but the concentration can rise manyfold upon acute inflammation. In its absence, neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema, or COPD (chronic obstructive pulmonary disease) in adults and cirrhosis in adults or children.
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 that can polymerise and accumulate in the liver (infantile hepatic cirrhosis).
Role in disease
Disorders of this protein include alpha 1-antitrypsin deficiency, an autosomal codominant hereditary disorder in which a deficiency of alpha 1-antitrypsin leads to a chronic uninhibited tissue breakdown. This causes the degradation especially of lung tissue, and eventually leads to characteristic manifestations of pulmonary emphysema. Evidence has shown that cigarette smoke can lead to oxidation of methionine 358 of α1-antitrypsin (382 in the pre-processed form containing the 24 amino acid signal peptide), a residue essential for binding elastase; this is thought to be one of the primary mechanisms by which cigarette smoking (or second-hand smoke) can lead to emphysema. Because A1AT is expressed in the liver, certain mutations in the gene encoding the protein can cause misfolding and impaired secretion, which can lead to liver cirrhosis.
An extremely rare form of Pi, termed PiPittsburgh, functions as an antithrombin (a related serpin), due to a mutation (Met358Arg). One person with this mutation has been reported to have died of a lethal bleeding diathesis.
Liver biopsy will show abundant PAS-positive globules within periportal hepatocytes.
The protein was originally named "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 protein'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 100 different variants of α1-antitrypsin have been described in various populations. North-Western Europeans are most at risk for carrying one of the most common mutant forms of A1AT, the Z mutation (Glu342Lys on M1A, rs28929474).
A1AT is a single-chain glycoprotein consisting of 394 amino acids in the mature form and exhibits a number of glycoforms. 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.
The level of A1AT in serum is most often determined by adding an antibody that binds to A1AT, then using turbidimetry to measure how much A1AT is present. Other detection methods include use of enzyme-linked-immuno-sorbent-assays and radial immunodiffusion.
Different analytical methods are used to determine A1AT phenotype. As protein electrophoresis is imprecise, A1AT phenotype is analysed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point or charge in a pH gradient.
Normal A1AT is termed M, as it is migrates toward the center of such an IEF gel. 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 IEF can signify the presence of alpha 1-antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above.
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, whereas 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 (366 in pre-processed form)
- PiS is caused by a glutamate to valine mutation at position 264 (288 in pre-processed form)
Other rarer forms have been described; in all there are over 80 variants.
|Systematic (IUPAC) name|
|CAS Registry Number|
|Molecular mass||44324.5 g/mol|
|(what is this?)|
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 US FDA has approved the use of three alpha 1-antitrypsin products derived from a human plasma: Prolastin, Zemaira, and Aralast. These products for intravenous augmentation 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. However, inhaled A1AT may not reach the elastin fibers in the lung where elastase injury actually occurs. Further study is currently underway.
- Gettins PG (Dec 2002). "Serpin structure, mechanism, and function". Chemical Reviews 102 (12): 4751–804. doi:10.1021/cr010170. PMID 12475206.
- Kushner, Mackiewicz A (1993). The acute phase response: an overview. Acute-phase glycoproteins: molecular biology, biochemistry and clinical applications (CRC Press). pp. 3–19.
- DeMeo DL, Silverman EK (Mar 2004). "Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk". Thorax 59 (3): 259–64. doi:10.1136/thx.2003.006502. PMC 1746953. PMID 14985567.
- Taggart, C., Cervantes-Laurean, D., Kim, G., McElvaney, N. G., Wehr, N., Moss, J., & Levine, R. L. (2000). Oxidation of either Methionine 351 or Methionine 358 in α1-Antitrypsin Causes Loss of Anti-neutrophil Elastase Activity. Journal of Biological Chemistry, 275(35), 27258–27265. doi:10.1074/jbc.M004850200
- Kolarich D, Weber A, Turecek PL, Schwarz HP, Altmann F (Jun 2006). "Comprehensive glyco-proteomic analysis of human alpha1-antitrypsin and its charge isoforms". Proteomics 6 (11): 3369–80. doi:10.1002/pmic.200500751. PMID 16622833.
- Alkins SA, O'Malley P (Mar 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. doi:10.1378/chest.117.3.875. PMID 10713018.
- Kolarich D, Turecek PL, Weber A, Mitterer A, Graninger M, Matthiessen P, Nicolaes GA, Altmann F, Schwarz HP (Nov 2006). "Biochemical, molecular characterization, and glycoproteomic analyses of alpha(1)-proteinase inhibitor products used for replacement therapy". Transfusion 46 (11): 1959–77. doi:10.1111/j.1537-2995.2006.01004.x. PMID 17076852.
- Axelsson U, Laurell CB (Nov 1965). "Hereditary variants of serum alpha-1-antitrypsin". American Journal of Human Genetics 17 (6): 466–72. PMC 1932630. PMID 4158556.
- Wu Y, Foreman RC (Apr 1991). "The molecular genetics of alpha 1 antitrypsin deficiency". BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology 13 (4): 163–9. doi:10.1002/bies.950130404. PMID 1859394.
- Kalsheker N (Apr 1989). "Alpha 1-antitrypsin: structure, function and molecular biology of the gene". Bioscience Reports 9 (2): 129–38. doi:10.1007/BF01115992. PMID 2669992.
- Crystal RG (Dec 1989). "The alpha 1-antitrypsin gene and its deficiency states". Trends in Genetics : TIG 5 (12): 411–7. doi:10.1016/0168-9525(89)90200-X. PMID 2696185. Check date values in:
|year= / |date= mismatch(help)
- Carrell RW, Jeppsson JO, Laurell CB, Brennan SO, Owen MC, Vaughan L, Boswell DR (Jul 1982). "Structure and variation of human alpha 1-antitrypsin". Nature 298 (5872): 329–34. doi:10.1038/298329a0. PMID 7045697.
- Elliott PR, Abrahams JP, Lomas DA (Jan 1998). "Wild-type alpha 1-antitrypsin is in the canonical inhibitory conformation". Journal of Molecular Biology 275 (3): 419–25. doi:10.1006/jmbi.1997.1458. PMID 9466920.
- Miyamoto Y, Akaike T, Maeda H (Mar 2000). "S-nitrosylated human alpha(1)-protease inhibitor". Biochimica Et Biophysica Acta 1477 (1-2): 90–7. doi:10.1016/S0167-4838(99)00264-2. PMID 10708851.
- Coakley RJ, Taggart C, O'Neill S, McElvaney NG (Jan 2001). "Alpha1-antitrypsin deficiency: biological answers to clinical questions". The American Journal of the Medical Sciences 321 (1): 33–41. doi:10.1097/00000441-200101000-00006. PMID 11202478.
- Lomas DA, Lourbakos A, Cumming SA, Belorgey D (Apr 2002). "Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia". Biochemical Society Transactions 30 (2): 89–92. doi:10.1042/BST0300089. PMID 12023831.
- Kalsheker N, Morley S, Morgan K (Apr 2002). "Gene regulation of the serine proteinase inhibitors alpha1-antitrypsin and alpha1-antichymotrypsin". Biochemical Society Transactions 30 (2): 93–8. doi:10.1042/BST0300093. PMID 12023832.
- Perlmutter DH (Dec 2002). "Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury". The Journal of Clinical Investigation 110 (11): 1579–83. doi:10.1172/JCI16787. PMC 151639. PMID 12464659. Check date values in:
|year= / |date= mismatch(help)
- Lomas DA, Mahadeva R (Dec 2002). "Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy". The Journal of Clinical Investigation 110 (11): 1585–90. doi:10.1172/JCI16782. PMC 151637. PMID 12464660. Check date values in:
|year= / |date= mismatch(help)
- Lisowska-Myjak B (Feb 2005). "AAT as a diagnostic tool". Clinica Chimica Acta; International Journal of Clinical Chemistry 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. doi:10.7861/clinmedicine.5-3-249. PMID 16011217.
- Rudnick DA, Perlmutter DH (Sep 2005). "Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease". Hepatology (Baltimore, Md.) 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". Clinical and Experimental Rheumatology 24 (2 Suppl 41): S82–91. PMID 16859601.
- The MEROPS online database for peptidases and their inhibitors: I04.001
- Proteopedia: Alpha-1-antitrypsin
- Alpha 1-antitrypsin at Lab Tests Online