A1AT not only binds to neutrophil elastase from inflammatory cells but also to elastase on the cell surface. In this latter role, elastase acts as a signaling molecule for cell movement, rather than as an enzyme.[6] Besides liver cells, A1PI is also produced in bone marrow, lymphoid tissue, and the Paneth cells of the gut.[7]
Inactivation of A1AT by other enzymes during inflammation or infection can halt T cell migration precisely at the site of the pathological insult. This suggests that α1PI plays a key role in lymphocyte movement and immune surveillance, particularly in response to infection.[8]A1AT is bothan endogenous protease inhibitor andan exogenous one used as medication. Thepharmaceutical form is purified fromhuman donor blood and is sold under thenonproprietary name alpha1–proteinase inhibitor (human) and under various trade names (including Aralast NP, Glassia, Prolastin, Prolastin-C, and Zemaira).Recombinant versions are also available but are currently used inmedical research more than as medication.
The protein was initially named "antitrypsin" because of its ability to bind and irreversibly inactivate the enzymetrypsin in vitrocovalently. Trypsin, a type ofpeptidase, is a digestive enzyme active in theduodenum and elsewhere. In older biomedical literature it was sometimes calledserum trypsin inhibitor (STI, dated terminology), because its capability as atrypsin inhibitor was a salient feature of its early study.
The termalpha-1 refers to the protein's behavior onprotein electrophoresis. On electrophoresis, the protein component of the blood is separated byelectric current. There are severalclusters, the first beingalbumin, the second being thealpha, the thirdbeta and the fourthgamma (immunoglobulins). The non-albumin proteins are referred to asglobulins.
Thealpha region can be further divided into two sub-regions, termed "1" and "2". Alpha-1 antitrypsin is the mainprotein of thealpha-globulin 1 region.
Another name used isalpha-1 proteinase inhibitor (α1-PI).
Over 100 different variants of α1-antitrypsin have been described in various populations. North-WesternEuropeans are most at risk for carrying one of the most common mutant forms of A1AT, the Z mutation (Glu342Lys on M1A, rs28929474).[9]
A1AT is a single-chain glycoprotein consisting of 394 amino acids in the mature form and exhibits manyglycoforms. 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 theAsparagine 107 (UniProtKB amino acid nomenclature). Theseglycans carry different amounts of negatively charged sialic acids; this causes the heterogeneity observed on normal A1AT when analysed byisoelectric focusing. Also, the fucosylated triantennary N-glycans were shown to have thefucose as part of a so-calledSialyl Lewis xepitope,[10] which could confer thisprotein particular protein-cell recognition properties. The singlecysteine residue of A1AT in position 256 (UniProtKB nomenclature) is found to be covalently linked to a free singlecysteine by adisulfide bridge.[10]
A1AT is a 52-kDaserpin and, inmedicine, it is considered the most prominent serpin; the termsα1-antitrypsin andprotease inhibitor (Pi) are often used interchangeably.
Most serpins inactivateenzymes by binding to themcovalently. These enzymes are released locally in relatively low concentrations where they are immediately cleared by proteins such as A1AT. In theacute phase reaction, a further elevation is required to "limit" the damage caused by activatedneutrophil granulocytes and their enzymeelastase, which breaks down theconnective tissue fiberelastin.
Besides limiting elastase activity to limit tissue degradation, A1PI also acts to induce locomotion of lymphocytes through tissue including immature T cells through the thymus where immature T cells mature to become immunocompetent T cells that are released into tissue to elevate immune responsiveness.[11]
Disorders of this protein includealpha-1 antitrypsin deficiency, anautosomal co-dominanthereditary 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 ofpulmonary emphysema.[12] Evidence has shown[13] that cigarette smoke can result in oxidation ofmethionine 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 thegene encoding the protein can cause misfolding and impaired secretion, which can lead toliver cirrhosis.
An extremely rare form ofPi, termedPiPittsburgh, functions as anantithrombin (a relatedserpin), due to a mutation (Met358Arg). One person with this mutation has been reported to have died of ableeding diathesis.[14]
A liver biopsy will show abundantPAS-positive globules within periportal hepatocytes.
Patients withrheumatoid arthritis (RA) have been found to makeautoantibodies toward thecarbamylated form of A1AT in thesynovial fluid. This suggests that A1AT may play an anti-inflammatory or tissue-protecting role outside the lungs. These antibodies are associated with a more severe disease course, can be observed years before disease onset, and may predict the development of RA inarthralgia patients. Consequently, carbamylated A1AT is currently being developed as anantigenicbiomarker for RA.[15]
A1AT has areference range in blood of 0.9–2.3 g/L (in the US the reference range is expressed as mg/dL or micromoles), but the concentration can rise manyfold uponacute inflammation.[16]
The level of A1AT in serum is most often determined by adding an antibody that binds to A1AT, then usingturbidimetry to measure how much A1AT is present. Other detection methods include the use of enzyme-linked-immuno-sorbent-assays and radial immunodiffusion.
Different analytical methods are used to determine A1ATphenotype. Asproteinelectrophoresis is imprecise, the A1AT phenotype is analysed byisoelectric 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 apH gradient.
Normal A1AT is termedM, as it 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 ofalpha-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 twocopies of the A1ATgene, aheterozygote 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.
Inblood test results, the IEF results are notated as inPiMM, wherePi stands forprotease inhibitor and "MM" is the banding pattern of that patient.
Alpha-1 antitrypsin levels in the blood depend on thegenotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in theproteasome, whereas others have a tendency topolymerise, being retained in theendoplasmic reticulum. The serum levels of some of the common genotypes are:
Alpha-1 antitrypsin concentrates are prepared from theblood plasma of blood donors. The USFood and Drug Administration (FDA) has approved the use of four alpha-1 antitrypsin products derived from a human plasma: Prolastin, Zemaira, Glassia, and Aralast.[24][25][26][27][28][29] These products for intravenous augmentation A1AT therapy can cost up to $100,000 per year per patient.[31] They are administered intravenously at a dose of 60 mg/kg once a week; higher doses do not provide additional benefit although they can be used in anticipation of an interruption of weekly administration, such as for a vacation.[32]
Alpha1-proteinase inhibitor (Respreeza) was approved for medical use in the European Union in August 2015.[30] It is indicated for maintenance treatment, to slow the progression of emphysema in adults with documented severe alpha1-proteinase inhibitor deficiency (e.g., genotypes PiZZ, PiZ (null), Pi (null, null), PiSZ).[30] People are to be under optimal pharmacologic and non-pharmacologic treatment and show evidence of progressive lung disease (e.g. lower forced expiratory volume per second (FEV1) predicted, impaired walking capacity or increased number of exacerbations) as evaluated by a healthcare professional experienced in the treatment of alpha1-proteinase inhibitor deficiency.[30]
The most common side effects include dizziness, headache, dyspnoea (shortness of breath) and nausea.[30] Allergic reactions have been observed during treatment, some of which were severe.[30]
Aerosolized-augmented A1AT therapy is under study.[when?] This involves inhaling purified human A1AT into the lungs and trapping the A1AT into the lower respiratory tract. However, inhaled A1AT may not reach the elastin fibers in the lung where elastase injury occurs. Further study is currently underway.[33]Recombinant alpha-1 antitrypsin is not yet available for use as a medication but is under development.[34]
^"NM_001127701.1(SERPINA1):c.1096G>A (p.Glu366Lys)".ClinVar Genomic variation as it relates to human health. U.S. National Library of Medicine, National Insittues of Health.Archived from the original on 13 October 2022. Retrieved13 October 2022.Interpretation: Pathogenic risk factor
^abKolarich D, Weber A, Turecek PL, Schwarz HP, Altmann F (June 2006). "Comprehensive glyco-proteomic analysis of human alpha1-antitrypsin and its charge isoforms".Proteomics.6 (11):3369–80.doi:10.1002/pmic.200500751.PMID16622833.S2CID25498702.
^Owen MC, Brennan SO, Lewis JH, Carrell RW (September 1983). "Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder".The New England Journal of Medicine.309 (12):694–8.doi:10.1056/NEJM198309223091203.PMID6604220.
^Verheul MK, Yee A, Seaman A, Janssen GM, van Veelen PA, Drijfhout JW, et al. (June 2017). "Identification of carbamylated alpha 1 anti-trypsin (A1AT) as an antigenic target of anti-CarP antibodies in patients with rheumatoid arthritis".Journal of Autoimmunity.80:77–84.doi:10.1016/j.jaut.2017.02.008.PMID28291659.
^Mackiewicz A, Kushner I, Baumann H, eds. (1993). "Acute phase response: an overview".Acute phase proteins: molecular biology, biochemistry, and clinical applications. CRC Press. pp. 3–19.ISBN1-000-14197-7.OCLC1164833220.
^Alkins SA, O'Malley P (March 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.PMID10713018.
Kalsheker N (April 1989). "Alpha 1-antitrypsin: structure, function and molecular biology of the gene".Bioscience Reports.9 (2):129–38.doi:10.1007/BF01115992.PMID2669992.S2CID34243822.
Elliott PR, Abrahams JP, Lomas DA (January 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.PMID9466920.
Miyamoto Y, Akaike T, Maeda H (March 2000). "S-nitrosylated human alpha(1)-protease inhibitor".Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology.1477 (1–2):90–7.doi:10.1016/S0167-4838(99)00264-2.PMID10708851.
Coakley RJ, Taggart C, O'Neill S, McElvaney NG (January 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.PMID11202478.S2CID2458903.
Lomas DA, Lourbakos A, Cumming SA, Belorgey D (April 2002). "Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia".Biochemical Society Transactions.30 (2):89–92.doi:10.1042/BST0300089.PMID12023831.
Kalsheker N, Morley S, Morgan K (April 2002). "Gene regulation of the serine proteinase inhibitors alpha1-antitrypsin and alpha1-antichymotrypsin".Biochemical Society Transactions.30 (2):93–8.doi:10.1042/BST0300093.PMID12023832.
Lisowska-Myjak B (February 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.PMID15653097.
.png)
This article incorporates text from this source, which is in thepublic domain.
