Alpha 1-antitrypsin
Serine Protease Inhibitors (Serpins)

Author: monica mangioni
Date: 13/12/2007

Description

DEFINITION

Alpha-1 antitrypsin is a 52-kDa serum glycoprotein. It is the main blood-borne serine protease inhibitor of a broad range of proteases: destructive neutrophil proteases including elastase, catepsin G, proteinase 3, pancreatic elastase and trypsin, chymotrypsin and skin and synovial collagenases. Its primary function is the inhibition of neutrophil elastase.

THE GENE

DatabaseLink
SymbolsA1A; A1AT; AAT; ANTITRYPSIN;
SERPINA1;
PROTEASE INHIBITOR 1, PI;
ANTI-ELASTASE
WikigenesSERPINA1
GeneCardsSERPINA1
Your Favorite Gene SigmaSERPINA1
Uni-ProtA1AT_HUMAN

CHEMICAL STRUCTURE AND IMAGES

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

Protein Aminoacids Percentage

SYNTHESIS AND TURNOVER

mRNA synthesis
protein synthesis

post-translational modifications
degradation

CELLULAR FUNCTIONS

cellular localization,
biological function

  • Enzymes
DatabaseLink
BRENDA - The Comprehensive Enzyme Information System"URL":
KEGG Pathways"URL":
Human Metabolome Database"URL":
  • Cell signaling and Ligand transport
  • Structural proteins

REGULATION

DIAGNOSTIC USE

Normal serum AAT concentration
Normal ranges of serum AAT vary significantly among:

  • age and gender: necessitate separate ranges
  • clinical laboratories: compared to reliable reference materials

Increase in serum AAT concentration
AAT, an acute phase reactant, is up-regulated during acute phase response to tissue necrosis and inflammation.
Serum levels increase in:

  • rheumatoid arthritis
  • bacterial infections
  • vasculitis
  • carcinomatosis
  • estrogen level rises after puberty
  • pregnancy
  • contraceptive medication use

In patients with acute AAT deficiency, an acute phase status does not induce a significant increase in the serum AAT level.

Serum AAT deficiency
The level of AAT in serum or plasma is controlled by a co-dominant gene located on chromosome 14q32.1, namely the Pi locus of the protease inhibitor.
As AAT phenotypes can be classified as ‘‘at risk’’ and ‘‘not at risk’’ for the development of emphysema, an AATserum level of less than or equal to 11 Amol/l is used as the serum AAT level that defines AAT deficiency.

AAT as a diagnostic tool in:

  • lung diseases
  • liver diseases
  • renal diseases
  • cardiovascular diseases
  • arterial aneurysm
  • vasculitides
  • panniculitis
  • gastrointestinal diseases
  • diabetes

DIAGNOSTIC PROCEDURES FOR DETECTING AAT

Full spectrum diagnostic testing for AAT deficiency recommended by the World Health Organization can be divided into four stages: immunoassay, phenotype, genotype, and function.
Suspect of AAT deficiency:

  1. Immunoassay test: Dried blood spot screening test, Faecal AAT
  2. Phenotyping
  3. Genotyping
  4. Evaluation of AAT functions in serum

ASSOCIATED DISEASE

Two types of problems often occur:

  1. Alpha1-antitrypsin can be defective, so that it is unable to block its proper target and leaves the protease to go on a rampage. This happens in emphysema and/or COPD , where alpha1-antitrypsin is compromised and elastase destroys connective tissue in the lungs. One way that the serpin can be disabled is through smoking, which can modify the methionine amino acid used as bait.
  2. Alternatively, the unique trapping mechanism of serpins, can lead to another problem. After the loop is broken, it can associate with other copies of the serpin, leading to bulky aggregates. If these form inside nerve cells, they can block nerve function and lead to dementia.

Alpha 1-antitrypsin deficiency (α1-antitryspin deficiency, A1AD or Alpha-1)

It is an inherited genetic disorder caused by defective production of alpha 1-antitrypsin (A1AT), leading to decreased A1AT activity.
There are several forms and degrees of deficiency.
Deficiency of AAT can lead to many clinical manifestations, most commonly a decline in lung function that include chronic obstructive pulmonary disease COPD, in the form of emphysema and bronchiectasis.
However, patients with this genetic disorder may also develop dysfunctions of other organs such as the liver, to intracellular deposition of excessive abnormal A1AT protein, and the skin in the form of panniculitis.

It is treated by avoidance of damaging inhalants, by intravenous infusions of the AAT protein, by transplantation of the liver or lungs, and by a variety of other measures, but it usually produces some degree of disability and reduced life expectancy.

SYNTHESIS

Plasma α1-AT is predominantly derived from the liver.
There is also evidence for extrahepatic sites of synthesis, notably that in blood monocytes and tissue macrophages as well as in enterocytes.

AAT gene:

It is located on chromosome 14q32.1 and is composed of 7 exons separated by 6 introns. There is a tissue-specific region promoter for liver and alternative promoters for other tissues.
Basal AAT expression is regulated by the synergistic action of the tissue-specific transcription factors hepatocyte nuclear factors 1α ( HNF1α ) and 4 ( HNF4 ).
The AAT gene contains at least two enhancer elements , one at the 5’ end of the gene and the other at the 3’ end. The 5’ enhancer is dominant under basal conditions and, following stimulation with IL-6 and related cytokines, both enhancers are essential and the 3’ enhancer plays a major role.

Interferon γ and transforming growth factor β also modulate the hepatocyte response to IL-6. In addition to cytokines having an effect on AAT gene regulation, dexamethasone and oestrogen may have a stimulatory effect on gene regulation.

Monocyte AAT production appears to be primarily under the control of IL-6, although lipopolysaccharide , interleukin-1β (IL-1β) and tumour necrosis factor α (TNFα) all cause a 2±3-fold increase in AAT production by peripheral blood monocytes.

CELLULAR FUNCTIONS

It is found in the bloodstream at 1.5 - 3.5 gram/liter. It is also a classical positive acute phase protein in that plasma concentrations increase three to fivefold during the host response to tissue injury and/or inflammation.
It protects tissues from enzymes of inflammatory cells, especially elastase and ensures that the elastase doesn't spread throughout the body.

MOLECULAR MECHANISM

Alpha 1-Antitrypsin is a metastable protein, meaning that it is only partially stable in their active form, but it can snap into a far more stable form when they find a protease. The key is a flexible loop. One amino acid in this loop, a methionine, is used as bait.
Proteases are trapped and this pulls the active site of elastase out of shape, so that it is no longer active.
It destabilizes the elastase, so that it partially unfolds. This makes it an easy target for the cellular machinery that cleans up defective proteins, which destroys both the protease and the one-shot serpin . Tripping the Trap

REGULATION AND DEREGULATION

Formation of the covalently stabilized α1-Antitrypsin-neutrophil elastase complex results in a structurally rearranged molecule possessing chemotactic activities and mediating increases in expression of the α1-AT gene in human monocytes and macrophages and hepatocytes and is more rapidly cleared from the circulation than is the native α1-AT molecule by endocytosis and lysosomal degradation.

α1-AT-elastase complexes is recognized by a specific serpin-enzyme complex (SEC) receptor that mediates increases in de novo synthesis of α1-AT in response to α1-AT-elastase complexes.
The SEC receptor recognizes a pentapeptide domain on α1-AT-elastase complexes (α1-AT 370-374), and the same domain in several other serpins, amyloid-β peptide, substance P, and other tachykinins and also α1-AT after it has undergone limited proteolysis by other important constituents of the inflammatory reaction including metallo-elastases.

The SEC receptor activates a signal transduction pathway for regulation of a1-AT gene expression and, therefore, modulates the net elastase/anti-elastase balance in the local microenvironment.

DIAGNOSTIC USE

Attachments
fileuserdate
A1AT-ch1.gifgp2011-09-25T00:00:00
A1AT-ch2.gifgp2011-09-25T00:00:00
Alpha_1_anti_trypsin.xlsmonica2007-12-13T00:00:00
aAT.gifmonica2007-12-13T00:00:00
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