Alpha-1 antitrypsin

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(Redirected from
Alpha 1-antitrypsin
)
SERPINA1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000197249
ENSG00000277377

ENSMUSG00000071177

UniProt

P01009

Q00897
P07758

RefSeq (mRNA)

NM_009246

RefSeq (protein)

NP_033272
NP_001239498
NP_033269

Location (UCSC)Chr 14: 94.38 – 94.39 MbChr 12: 103.73 – 103.74 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Alpha-1 antitrypsin or α1-antitrypsin (A1AT, α1AT, A1A, or AAT) is a protein belonging to the serpin superfamily. It is encoded in humans by the SERPINA1 gene. A protease inhibitor, it is also known as alpha1–proteinase inhibitor (A1PI) or alpha1-antiproteinase (A1AP) because it inhibits various proteases (not just trypsin).[5] 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. As a type of enzyme inhibitor, it protects tissues from enzymes of inflammatory cells, especially neutrophil elastase, and has a 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 inflammation.[6]

When the

alpha-1 antitrypsin deficiency), neutrophil elastase is excessively free to break down elastin, degrading the elasticity of the lungs, which results in respiratory complications, such as chronic obstructive pulmonary disease, in adults. Normally, A1AT leaves its site of origin, the liver, and joins the systemic circulation; defective A1AT can fail to do so, building up in the liver, which results in cirrhosis in either adults or children
.

In addition to binding to neutrophil elastase released by inflammatory cells, A1AT also binds to elastase localized on the cell surface in which case elastase does not act as an enzyme, but instead acts to signal cells to undergo locomotion.[7] Besides liver cells, A1PI is produced in bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut.[8]

Inactivation of A1AT by enzymes other than elastase due to inflammation/infection causes the migration of T cells to halt precisely at the site where the pathologic insult exists. This suggests a role for α1PI not only in locomotion of lymphocytes through tissue, but as a consequence of infection, a primary role as a sentinel in immune vigilance.[9]

A1AT is both

pharmaceutical form is purified from human donor blood and is sold under the nonproprietary 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 in medical research
more than as medication.

Function

A1AT is a 52-

kDa serpin and, in medicine, it is considered the most prominent serpin; the terms α1-antitrypsin and protease inhibitor
(Pi) are often used interchangeably.

Most serpins inactivate

neutrophil granulocytes 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.[10]

Like all

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

Alpha-1 antitrypsin (white) with highlighted 'reactive centre loop' (blue) and A-sheet (light blue). (PDB: 1QLP)
Main article: Alpha-1 antitrypsin deficiency

Disorders of this protein include

liver cirrhosis
.

An extremely rare form of Pi, termed PiPittsburgh, functions as an

serpin), due to a mutation (Met358Arg). One person with this mutation has been reported to have died of a bleeding diathesis.[13]

A liver biopsy will show abundant PAS-positive globules within periportal hepatocytes.

Patients with

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 antigenic biomarker for RA.[14]

Nomenclature

The protein was initially named "antitrypsin" because of its ability to bind and irreversibly inactivate the enzyme

peptidase, is a digestive enzyme active in the duodenum
and elsewhere.

The term alpha-1 refers to the protein's behavior on

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

alpha-globulin
1 region.

Another name used is alpha-1 proteinase inhibitor (α1-PI).

Genetics

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

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).[15]

Biochemical properties

A1AT is a single-chain glycoprotein consisting of 394 amino acids in the mature form and exhibits many

disulfide bridge.[16]

Analysis

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
. 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

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 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, whereas 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.

Medical uses

Alpha-1 antitrypsin
Clinical data
Trade namesAralast, Zemaira, Glassia, others[17]
AHFS/Drugs.comMonograph
License data
Intravenous
ATC code
Legal status
Legal status
Identifiers
  • Alpha-1-proteinase inhibitor
ECHA InfoCard
100.029.919 Edit this at Wikidata
Chemical and physical data
FormulaC2001H3130N514O601S10
Molar mass44324.65 g·mol−1
  (verify)

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.[24][25][26][27][28][29] These products for intravenous augmentation A1AT therapy can cost up to $100,000 per year per patient.[30] 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.[31]

Alpha1-proteinase inhibitor (Respreeza) was approved for medical use in the European Union in August 2015.[32] 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).[32] 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.[32]

The most common side effects include dizziness, headache, dyspnoea (shortness of breath) and nausea.[32] Allergic reactions have been observed during treatment, some of which were severe.[32]

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.[when?][citation needed] Recombinant alpha-1 antitrypsin is not yet available for use as a medication but is under development.[when?]

History

Axelsson and Laurell first investigated the possibility of allelic variants of A1AT leading to disease in 1965.[33]

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

  1. ^ a b c ENSG00000277377 GRCh38: Ensembl release 89: ENSG00000197249, ENSG00000277377 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000071177 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. PMID 12475206
    .
  6. ^ Kushner, Mackiewicz A (1993). The acute phase response: an overview. CRC Press. pp. 3–19. {{cite book}}: |work= ignored (help)
  7. PMID 25351931
    .
  8. PMID 15795238
    .
  9. PMID 28626366
    .
  10. PMID 12225788
    .
  11. PMID 14985567
    .
  12. PMID 10867014
    .
  13. PMID 6604220
    .
  14. PMID 28291659
    .
  15. ^ "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 2022-10-13. Retrieved 2022-10-13. Interpretation: Pathogenic risk factor
  16. ^
    S2CID 25498702
    .
  17. ^ "Alpha-1-Proteinase Inhibitor, Human". Drugs.com. 4 May 2020. Archived from the original on 3 October 2020. Retrieved 11 May 2020.
  18. ^ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 9 April 2023.
  19. ^ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
  20. ^ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
  21. ^ "Health product highlights 2021: Annexes of products approved in 2021". Health Canada. 3 August 2022. Retrieved 25 March 2024.
  22. ^ "Regulatory Decision Summary for Pronextica Liquid". Drug and Health Products Portal. 14 November 2023. Retrieved 1 April 2024.
  23. ^ "Respreeza - Summary of Product Characteristics (SmPC)". (emc). 10 October 2018. Archived from the original on 3 October 2020. Retrieved 11 May 2020.
  24. ^ a b "Aralast NP". U.S. Food and Drug Administration (FDA). 22 July 2017. Archived from the original on 10 August 2020. Retrieved 11 May 2020.
  25. ^ a b "Aralast". U.S. Food and Drug Administration (FDA). 22 July 2017. Archived from the original on 4 August 2020. Retrieved 11 May 2020.
  26. ^ a b "Glassia". U.S. Food and Drug Administration (FDA). 22 July 2017. Archived from the original on 1 April 2020. Retrieved 11 May 2020.
  27. ^ a b "Prolastin". U.S. Food and Drug Administration (FDA). 5 March 2018. Archived from the original on 28 September 2020. Retrieved 11 May 2020.
  28. ^ a b "Prolastin-C". U.S. Food and Drug Administration (FDA). 21 September 2017. Archived from the original on 3 October 2020. Retrieved 11 May 2020.
  29. ^ a b "Zemaira". U.S. Food and Drug Administration (FDA). 22 July 2017. Archived from the original on 1 April 2020. Retrieved 11 May 2020.
  30. PMID 10713018
    .
  31. PMID 30775428
    .
  32. ^ a b c d e "Respreeza EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 3 October 2020. Retrieved 11 May 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  33. PMID 4158556.[citation needed
    ]

Further reading

External links
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