View source for Alpha-1 antitrypsin

{{Short description|Mammalian protein found in Homo sapiens}}
{{Use dmy dates|date=June 2024}}
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{{Infobox_gene}} 
'''Alpha-1 antitrypsin''' or '''α<sub>1</sub>-antitrypsin''' ('''A1AT''', '''α<sub>1</sub>AT''', '''A1A''', or '''AAT''') is a [[protein]] belonging to the [[serpin]] superfamily. It is encoded in humans by the ''SERPINA1'' [[gene]]. A [[protease inhibitor (biology)|protease inhibitor]], it is also known as '''alpha<sub>1</sub>–proteinase inhibitor''' ('''A1PI''') or '''alpha<sub>1</sub>-antiproteinase''' ('''A1AP''') because it inhibits various [[protease]]s (not just [[trypsin]]).<ref name=Gettins_2002>{{cite journal | vauthors = Gettins PG | title = Serpin structure, mechanism, and function | journal = Chemical Reviews | volume = 102 | issue = 12 | pages = 4751–804 | date = December 2002 | pmid = 12475206 | doi = 10.1021/cr010170 }}</ref>  As a type of [[enzyme inhibitor]], it protects [[tissue (biology)|tissues]] from [[enzyme]]s of [[inflammation|inflammatory]] cells, especially [[neutrophil elastase]].

When the [[blood]] contains inadequate or defective A1AT (as in [[alpha 1-antitrypsin deficiency|alpha-1 antitrypsin deficiency]]), neutrophil elastase can excessively break down [[elastin]], leading to the loss of [[elasticity (physics)|elasticity]] in the [[lung]]s. This results in [[pulmonology|respiratory issues]], such as [[chronic obstructive pulmonary disease]], in adults. Normally, A1AT is produced in the [[liver]] and enters the [[circulatory system#Systemic circulation|systemic circulation]]. However, defective A1AT may accumulate in the liver, potentially causing [[cirrhosis]] in both adults and [[pediatrics|children]].

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.<ref>{{cite journal | vauthors = Guttman O, Baranovski BM, Schuster R, Kaner Z, Freixo-Lima GS, Bahar N, Mizrahi MI, Brami I, Ochayon DE, Lewis EC | title = Acute-phase protein α1-anti-trypsin: diverting injurious innate and adaptive immune responses from non-authentic threats | journal = Clinical & Experimental Immunology | volume = 179 | issue = 2 | pages = 161–172 | date = February 2015 | pmid = 25351931 | pmc = 4298394 | doi = 10.1111/cei.12476 }}</ref> Besides liver cells, A1PI is also produced in bone marrow, lymphoid tissue, and the Paneth cells of the gut.<ref>{{cite journal | vauthors = Winkler IG, Hendy J, Coughlin P, Horvath A, Lévesque JP | title = Serine protease inhibitors serpina1 and serpina3 are down-regulated in bone marrow during hematopoietic progenitor mobilization | journal = The Journal of Experimental Medicine | volume = 201 | issue = 7 | pages = 1077–88 | date = April 2005 | pmid = 15795238 | pmc = 2213124 | doi = 10.1084/jem.20042299 }}</ref>

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.<ref>{{cite journal | vauthors = Richler R, Forssmann W, Henschler R | title = Current developments in mobilization of hematopoietic stem and progenitor cells and their interaction with niches in bone marrow | journal = Transfus Med Hemother | volume = 44 | issue = 3 | pages = 151–164 | date = June 2017 | pmid = 28626366 | pmc = 5473067 | doi = 10.1159/000477262 }}</ref>
A1AT is both [[protease inhibitor (biology)|an endogenous protease inhibitor]] and [[protease inhibitor (pharmacology)|an exogenous one used as medication]]. The [[pharmaceutical drug|pharmaceutical]] form is purified from [[blood donation|human donor blood]] and is sold under the [[drug nomenclature#Nonproprietary (generic) names|nonproprietary name]] alpha<sub>1</sub>–proteinase inhibitor (human) and under various trade names (including <!-- alphabetical order --> Aralast NP, Glassia, Prolastin, Prolastin-C, and Zemaira). [[Recombinant DNA|Recombinant]] versions are also available but are currently used in [[medical research]] more than as medication.

==Nomenclature==
The protein was initially named "antitrypsin" because of its ability to bind and irreversibly inactivate the enzyme [[trypsin]] in vitro [[covalent]]ly. Trypsin, a type of [[peptidase]], is a digestive enzyme active in the [[duodenum]] and elsewhere. In older biomedical literature it was sometimes called '''serum trypsin inhibitor''' (STI, dated terminology), because its capability as a [[trypsin inhibitor]] was a salient feature of its early study.

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 [[serum albumin|albumin]], the second being the ''alpha'', the third ''beta'' and the fourth ''gamma'' ([[immunoglobulin]]s). The non-albumin proteins are referred to as [[globulin]]s.

The ''alpha'' region can be further divided into two sub-regions, termed "1" and "2". Alpha-1 antitrypsin is the main [[protein]] of the [[alpha-globulin]] 1 region.

Another name used is ''alpha-1 proteinase inhibitor'' (α<sub>1</sub>-PI).

== Genetics ==
The [[gene]] is located on the long arm of [[chromosome 14]] (14q32.1).

Over 100 different variants of α<sub>1</sub>-antitrypsin have been described in various populations. North-Western [[Europe]]ans are most at risk for carrying one of the most common mutant forms of A1AT, the Z mutation (Glu342Lys on M1A, rs28929474).<ref>{{cite web | title = NM_001127701.1(SERPINA1):c.1096G>A (p.Glu366Lys) | url = https://www.ncbi.nlm.nih.gov/clinvar/variation/17967/?new_evidence=true | quote = Interpretation: Pathogenic risk factor | work = ClinVar Genomic variation as it relates to human health | publisher = U.S. National Library of Medicine, National Insittues of Health | access-date = 13 October 2022 | archive-date = 13 October 2022 | archive-url = https://web.archive.org/web/20221013133622/https://www.ncbi.nlm.nih.gov/clinvar/variation/17967/?new_evidence=true | url-status = live }}</ref>

== Structure ==
A1AT is a single-chain glycoprotein consisting of 394 amino acids in the mature form and exhibits many [[glycoform]]s. 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 ([[UniProtKB]] 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 focusing]]. Also, the fucosylated triantennary N-glycans were shown to have the [[fucose]] as part of a so-called [[Sialyl Lewis x]] [[epitope]],<ref name=Kolarich_2006>{{cite journal | vauthors = 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 | volume = 6 | issue = 11 | pages = 3369–80 | date = June 2006 | pmid = 16622833 | doi = 10.1002/pmic.200500751 | s2cid = 25498702 }}</ref> which could confer this [[protein]] particular protein-cell recognition properties. The single [[cysteine]] residue of A1AT in position 256 ([[UniProtKB]] nomenclature) is found to be covalently linked to a free single [[cysteine]] by a [[disulfide bridge]].<ref name=Kolarich_2006/>

== Function ==
A1AT is a 52-[[kDa]] [[serpin]] and, in [[medicine]], it is considered the most prominent serpin; the terms ''α1-antitrypsin'' and ''[[protease inhibitor (biology)|protease inhibitor]]'' (''P<sub>i</sub>'') are often used interchangeably.

Most serpins inactivate [[enzyme]]s by binding to them [[covalent]]ly. These enzymes are released locally in relatively low concentrations where they are immediately cleared by proteins such as A1AT. In the [[acute phase protein|acute phase reaction]], a further elevation is required to "limit" the damage caused by activated [[neutrophil granulocyte]]s and their enzyme [[elastase]], which breaks down the [[connective tissue]] fiber [[elastin]].

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.<ref>{{cite journal | vauthors = Lapidot T, Petit I | title = Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells | journal = Exp Hematol | volume = 30 | issue = 9 | pages = 973–981 | date = September 2012 | pmid = 12225788 | doi = 10.1016/s0301-472x(02)00883-4 | doi-access = free }}</ref>

Like all [[serine protease inhibitor]]s, A1AT has a characteristic [[secondary structure]] of [[beta sheet]]s and [[alpha helix|alpha helices]]. [[Mutation]]s in these areas can lead to non-functional proteins that can [[polymer]]ise and accumulate in the [[liver]] (infantile hepatic cirrhosis).

== Clinical significance ==
[[File:Alpha 1-antitrypsin (labelled).png|thumb|Alpha-1 antitrypsin (white) with highlighted 'reactive centre loop' (blue) and A-sheet (light blue). (PDB: 1QLP)]]
{{main|Alpha-1 antitrypsin deficiency}}
Disorders of this protein include [[alpha 1-antitrypsin deficiency|alpha-1 antitrypsin deficiency]], an [[Dominance (genetics)#Co-dominance|autosomal co-dominant]] [[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 [[emphysema|pulmonary emphysema]].<ref name=DeMeo_2004>{{cite journal | vauthors = 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 | volume = 59 | issue = 3 | pages = 259–64 | date = March 2004 | pmid = 14985567 | pmc = 1746953 | doi = 10.1136/thx.2003.006502 }}
</ref> Evidence has shown<ref>{{cite journal | vauthors = Taggart C, Cervantes-Laurean D, Kim G, McElvaney NG, Wehr N, Moss J, Levine RL | title = Oxidation of either methionine 351 or methionine 358 in alpha 1-antitrypsin causes loss of anti-neutrophil elastase activity | journal = The Journal of Biological Chemistry | volume = 275 | issue = 35 | pages = 27258–65 | date = September 2000 | pmid = 10867014 | doi = 10.1074/jbc.M004850200 | doi-access = free }}</ref> that cigarette smoke can result in oxidation of [[methionine]] 358 of α<sub>1</sub>-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 ''P<sub>i</sub>'', termed ''P<sub>i</sub>''<sub>Pittsburgh</sub>, functions as an [[antithrombin]] (a related [[serine protease inhibitor|serpin]]), due to a mutation ([[Methionine|Met]]358[[Arginine|Arg]]). One person with this mutation has been reported to have died of a [[bleeding diathesis]].<ref>{{cite journal | vauthors = Owen MC, Brennan SO, Lewis JH, Carrell RW | title = Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder | journal = The New England Journal of Medicine | volume = 309 | issue = 12 | pages = 694–8 | date = September 1983 | pmid = 6604220 | doi = 10.1056/NEJM198309223091203 }}</ref>

A liver biopsy will show abundant [[Periodic acid–Schiff stain|PAS]]-positive globules within periportal hepatocytes.

Patients with [[rheumatoid arthritis]] (RA) have been found to make [[Autoantibody|autoantibodies]] toward the [[Carbamylation|carbamylated]] form of A1AT in the [[synovial 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 in [[arthralgia]] patients. Consequently, carbamylated A1AT is currently being developed as an [[antigen]]ic [[biomarker]] for RA.<ref name=Verheul_2017>{{cite journal | vauthors = Verheul MK, Yee A, Seaman A, Janssen GM, van Veelen PA, Drijfhout JW, Toes RE, Mahler M, Trouw LA | title = Identification of carbamylated alpha 1 anti-trypsin (A1AT) as an antigenic target of anti-CarP antibodies in patients with rheumatoid arthritis | journal = Journal of Autoimmunity | volume = 80 | pages = 77–84 | date = June 2017 | pmid = 28291659 | doi = 10.1016/j.jaut.2017.02.008 }}</ref>

== Analysis ==
A1AT has a [[reference ranges for blood tests#Acute phase proteins|reference 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 upon [[acute-phase protein|acute inflammation]].<ref name=Kushner_1993>{{cite book | veditors = Mackiewicz A, Kushner I, Baumann H |chapter=Acute phase response: an overview |title=Acute phase proteins: molecular biology, biochemistry, and clinical applications |publisher=CRC Press |date=1993 |isbn=1-000-14197-7 |pages=3–19 |oclc=1164833220}}</ref> 

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 the use of enzyme-linked-immuno-sorbent-assays and radial immunodiffusion.

Different analytical methods are used to determine A1AT [[phenotype]]. As [[protein]] [[electrophoresis]] is imprecise, the 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 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|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 [[allele|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 IEF results are notated as in ''P<sub>i</sub>''MM, where ''P<sub>i</sub>'' stands for [[protease inhibitor (biology)|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]], whereas others have a tendency to [[polymer]]ise, 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|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.

== Medical uses ==
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Alpha-1 antitrypsin concentrates are prepared from the [[blood plasma]] of blood donors. The US [[Food and Drug Administration]] (FDA) has approved the use of four alpha-1 antitrypsin products derived from a human plasma: Prolastin, Zemaira, Glassia, and Aralast.<ref name="Aralast NP">{{cite web | title=Aralast NP | website=U.S. [[Food and Drug Administration]] (FDA) | date=22 July 2017 | url=https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/aralast-np | access-date=11 May 2020 | archive-date=10 August 2020 | archive-url=https://web.archive.org/web/20200810223748/https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/aralast-np | url-status=dead }}</ref><ref name="Aralast">{{cite web | title=Aralast | website=U.S. [[Food and Drug Administration]] (FDA) | date=22 July 2017 | url=https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/aralast | access-date=11 May 2020 | archive-date=4 August 2020 | archive-url=https://web.archive.org/web/20200804001929/https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/aralast | url-status=dead }}</ref><ref name="Glassia">{{cite web | title=Glassia | website=U.S. [[Food and Drug Administration]] (FDA) | date=22 July 2017 | url=https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/glassia | access-date=11 May 2020 | archive-date=1 April 2020 | archive-url=https://web.archive.org/web/20200401234108/https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/glassia | url-status=dead }}</ref><ref name="Prolastin">{{cite web | title=Prolastin | website=U.S. [[Food and Drug Administration]] (FDA) | date=5 March 2018 | url=https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/prolastin | access-date=11 May 2020 | archive-date=28 September 2020 | archive-url=https://web.archive.org/web/20200928040339/https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/prolastin | url-status=dead }}</ref><ref name="Prolastin-C">{{cite web | title=Prolastin-C | website=U.S. [[Food and Drug Administration]] (FDA) | date=21 September 2017 | url=https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/prolastin-c | access-date=11 May 2020 | archive-date=3 October 2020 | archive-url=https://web.archive.org/web/20201003030712/https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/prolastin-c | url-status=dead }}</ref><ref name="Zemaira">{{cite web | title=Zemaira | website=U.S. [[Food and Drug Administration]] (FDA) | date=22 July 2017 | url=https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/zemaira | access-date=11 May 2020 | archive-date=1 April 2020 | archive-url=https://web.archive.org/web/20200401234137/https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/zemaira | url-status=dead }}</ref> These products for intravenous augmentation A1AT therapy can cost up to $100,000 per year per patient.<ref name="Alkins_and_O'Malley_2000">{{cite journal | vauthors = 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 | volume = 117 | issue = 3 | pages = 875–80 | date = March 2000 | pmid = 10713018 | doi = 10.1378/chest.117.3.875 }}</ref> They are administered intravenously at a dose of 60&nbsp;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.<ref>{{cite journal | vauthors = Brantly ML, Lascano JE, Shahmohammadi A | title = Intravenous Alpha-1 Antitrypsin Therapy for Alpha-1 Antitrypsin Deficiency: The Current State of the Evidence | journal = Chronic Obstructive Pulmonary Diseases | volume = 6 | issue = 1 | pages = 100–114 | date = November 2018 | pmid = 30775428 | pmc = 6373587 | doi = 10.15326/jcopdf.6.1.2017.0185 }}</ref>

Alpha1-proteinase inhibitor (Respreeza) was approved for medical use in the European Union in August 2015.<ref name="Respreeza EPAR">{{cite web | title=Respreeza EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/respreeza | access-date=11 May 2020 | archive-date=3 October 2020 | archive-url=https://web.archive.org/web/20201003022345/https://www.ema.europa.eu/en/medicines/human/EPAR/respreeza | url-status=live }} {{PD-notice}}</ref> 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).<ref name="Respreeza EPAR" /> 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.<ref name="Respreeza EPAR" />

The most common side effects include dizziness, headache, dyspnoea (shortness of breath) and nausea.<ref name="Respreeza EPAR" /> Allergic reactions have been observed during treatment, some of which were severe.<ref name="Respreeza EPAR" />

Aerosolized-augmented A1AT therapy is under study.{{when|date=May 2020}} 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.<ref>{{cite journal |vauthors=Usmani OS |title=Feasibility of Aerosolized Alpha-1 Antitrypsin as a Therapeutic Option |journal=Chronic Obstr Pulm Dis |volume=7 |issue=3 |pages=272–9 |date=July 2020 |pmid=32726075 |pmc=7857706 |doi=10.15326/jcopdf.7.3.2019.0179 }}</ref> [[Recombinant DNA|Recombinant]] alpha-1 antitrypsin is not yet available for use as a medication but is under development.<ref>{{cite journal |vauthors=Bianchera A, Alomari E, Michielon A, Bazzoli G, Ronda N, Pighini G, Zanotti I, Giorgio C, Mozzarelli A, Bettini R, Bruno S |title=Recombinant Alpha-1 Antitrypsin as Dry Powder for Pulmonary Administration: A Formulative Proof of Concept |journal=Pharmaceutics |volume=14 |issue=12 |date=December 2022 |page=2754 |pmid=36559248 |pmc=9784676 |doi=10.3390/pharmaceutics14122754 |doi-access=free }}</ref>

== History ==
Axelsson and [[Carl-Bertil Laurell|Laurell]] first investigated the possibility of [[allele|allelic]] variants of A1AT leading to disease in 1965.<ref name=Axelsson_1965>{{cite journal | vauthors = Axelsson U, Laurell CB | title = Hereditary variants of serum alpha-1-antitrypsin | journal = American Journal of Human Genetics | volume = 17 | issue = 6 | pages = 466–72 | date = November 1965 | pmid = 4158556 | pmc = 1932630 }}{{Citation needed|reason=please give a reliable source for this assertion. Correct citation would be Eriksson and Laurell in 1963!|date=March 2009}}</ref>

== See also ==
* [[Alpha 1-antichymotrypsin]], another serpin that is analogous for protecting the body from excessive effects of its own inflammatory proteases
* [[Orosomucoid]] is a related alpha 1 protein 

== References ==
{{reflist}}

== Further reading ==
{{refbegin|33em}}
* Alpha-1 Antitrypsin. Methods in Molecular Biology. Edited by Cynthia L. Bristow. New York: Humana, 2023. doi:https://doi.org/10.1007/978-1-0716-3605-3.
* {{cite journal | vauthors = Kalsheker N | s2cid = 34243822 | title = Alpha 1-antitrypsin: structure, function and molecular biology of the gene | journal = Bioscience Reports | volume = 9 | issue = 2 | pages = 129–38 | date = April 1989 | pmid = 2669992 | doi = 10.1007/BF01115992 }}
* {{cite journal | vauthors = Crystal RG | title = The alpha 1-antitrypsin gene and its deficiency states | journal = Trends in Genetics | volume = 5 | issue = 12 | pages = 411–7 | date = December 1989 | pmid = 2696185 | doi = 10.1016/0168-9525(89)90200-X }}
* {{cite journal | vauthors = Carrell RW, Jeppsson JO, Laurell CB, Brennan SO, Owen MC, Vaughan L, Boswell DR | s2cid = 11904305 | title = Structure and variation of human alpha 1-antitrypsin | journal = Nature | volume = 298 | issue = 5872 | pages = 329–34 | date = July 1982 | pmid = 7045697 | doi = 10.1038/298329a0 | bibcode = 1982Natur.298..329C }}
* {{cite journal | vauthors = Elliott PR, Abrahams JP, Lomas DA | title = Wild-type alpha 1-antitrypsin is in the canonical inhibitory conformation | journal = Journal of Molecular Biology | volume = 275 | issue = 3 | pages = 419–25 | date = January 1998 | pmid = 9466920 | doi = 10.1006/jmbi.1997.1458 }}
* {{cite journal | vauthors = Miyamoto Y, Akaike T, Maeda H | title = S-nitrosylated human alpha(1)-protease inhibitor | journal = Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology | volume = 1477 | issue = 1–2 | pages = 90–7 | date = March 2000 | pmid = 10708851 | doi = 10.1016/S0167-4838(99)00264-2 }}
* {{cite journal | vauthors = Coakley RJ, Taggart C, O'Neill S, McElvaney NG | title = Alpha1-antitrypsin deficiency: biological answers to clinical questions | journal = The American Journal of the Medical Sciences | volume = 321 | issue = 1 | pages = 33–41 | date = January 2001 | pmid = 11202478 | doi = 10.1097/00000441-200101000-00006 | s2cid = 2458903 }}
* {{cite journal | vauthors = Lomas DA, Lourbakos A, Cumming SA, Belorgey D | title = Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia | journal = Biochemical Society Transactions | volume = 30 | issue = 2 | pages = 89–92 | date = April 2002 | pmid = 12023831 | doi = 10.1042/BST0300089 }}
* {{cite journal | vauthors = Kalsheker N, Morley S, Morgan K | title = Gene regulation of the serine proteinase inhibitors alpha1-antitrypsin and alpha1-antichymotrypsin | journal = Biochemical Society Transactions | volume = 30 | issue = 2 | pages = 93–8 | date = April 2002 | pmid = 12023832 | doi = 10.1042/BST0300093 }}
* {{cite journal | vauthors = Perlmutter DH | title = Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury | journal = The Journal of Clinical Investigation | volume = 110 | issue = 11 | pages = 1579–83 | date = December 2002 | pmid = 12464659 | pmc = 151639 | doi = 10.1172/JCI16787 }}
* {{cite journal | vauthors = Lomas DA, Mahadeva R | title = Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy | journal = The Journal of Clinical Investigation | volume = 110 | issue = 11 | pages = 1585–90 | date = December 2002 | pmid = 12464660 | pmc = 151637 | doi = 10.1172/JCI16782 }}
* {{cite journal | vauthors = Lisowska-Myjak B | title = AAT as a diagnostic tool | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 352 | issue = 1–2 | pages = 1–13 | date = February 2005 | pmid = 15653097 | doi = 10.1016/j.cccn.2004.03.012 }}
* {{cite journal | vauthors = Lomas DA | title = Molecular mousetraps, alpha1-antitrypsin deficiency and the serpinopathies | journal = Clinical Medicine | volume = 5 | issue = 3 | pages = 249–57 | year = 2005 | pmid = 16011217 | pmc = 4952210 | doi = 10.7861/clinmedicine.5-3-249 }}
* {{cite journal | vauthors = 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 | date = September 2005 | pmid = 16044402 | doi = 10.1002/hep.20815 | s2cid = 37875821 | doi-access = free }}
{{refend}}

== External links ==
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=I04.001 I04.001] {{Webarchive|url=https://web.archive.org/web/20080401023027/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=I04.001 |date=1 April 2008 }}
* [http://proteopedia.org/wiki/index.php/Alpha-1-antitrypsin Proteopedia: ''Alpha-1-antitrypsin'']
* {{UCSC gene info|SERPINA1}}

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