Alpha 1-antitrypsin
Encyclopedia
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.
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 enzyme
s 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 granulocyte
s 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 sheet
s and 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).
, a 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, 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 (Met
358Arg
). 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.
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 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 (α1-PI).
is located on the long arm of the fourteenth chromosome
(14q32.1).
Over 100 different variants of α1-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).
. 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.
electrophoresis
is imprecise, A1AT 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.
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.
Other detection methods include use of enzyme-linked-immuno-sorbent-assays in vitro and radial immunodiffusion.
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:
Other rarer forms have been described; in all there are over 80 variants.
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 augmention 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.
variants of A1AT leading to disease was first investigated by Axelsson and Laurell
in 1965.
Protease inhibitor (biology)
In biology and biochemistry, protease inhibitors are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins....
belonging to the serpin
Serpin
Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. The acronym serpin was originally coined because many serpins inhibit chymotrypsin-like serine proteases .The first members of the serpin superfamily to be extensively...
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
Reference range
In health-related fields, a reference range or reference interval usually describes the variations of a measurement or value in healthy individuals...
in blood of 1.5 - 3.5 gram
Gram
The gram is a metric system unit of mass....
/liter
Litre
pic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre...
(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
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...
, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema
Emphysema
Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
, or COPD
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease , also known as chronic obstructive lung disease , chronic obstructive airway disease , chronic airflow limitation and chronic obstructive respiratory disease , is the co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases...
(chronic obstructive pulmonary disease) in adults and cirrhosis in adults or children.
Function
A1AT is a 52-kDaKDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...
serpin
Serpin
Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. The acronym serpin was originally coined because many serpins inhibit chymotrypsin-like serine proteases .The first members of the serpin superfamily to be extensively...
and, in medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
, it is considered the most prominent serpin; the terms α1-antitrypsin and protease inhibitor
Protease inhibitor (biology)
In biology and biochemistry, protease inhibitors are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins....
(Pi) are often used interchangeably.
Most serpins inactivate enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s by binding to them covalently, requiring very high levels to perform their function. In the acute phase reaction
Acute phase protein
Acute-phase proteins are a class of proteins whose plasma concentrations increase or decrease in response to inflammation...
, a further elevation is required to "limit" the damage caused by activated neutrophil granulocyte
Neutrophil granulocyte
Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They are generally referred to as either neutrophils or polymorphonuclear neutrophils , and are subdivided into segmented neutrophils and banded neutrophils...
s and their enzyme elastase
Elastase
In molecular biology, elastase is an enzyme from the class of proteases that break down proteins.- Forms and classification:There exist eight human genes for elastase:Bacterial forms: Organisms such as P...
, which breaks down the connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...
fiber elastin
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...
.
Like all serine protease inhibitors, A1AT has a characteristic secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
of beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
s and alpha helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
. Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in these areas can lead to non-functional proteins that can polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
ise and accumulate in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
(infantile hepatic cirrhosis).
Role in disease
Disorders of this protein include alpha 1-antitrypsin deficiencyAlpha 1-antitrypsin deficiency
Alpha 1-antitrypsin deficiency is an autosomal recessive genetic disorder caused by defective production of alpha 1-antitrypsin , leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT protein in liver cells...
, a 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
Emphysema
Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
. Evidence has shown that cigarette smoke can lead to oxidation of methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
358 of α1-antitrypsin, 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
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
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
Antithrombin
Antithrombin is a small protein molecule that inactivates several enzymes of the coagulation system. Antithrombin is a glycoprotein produced by the liver and consists of 432 amino acids. It contains three disulfide bonds and a total of four possible glycosylation sites...
(a related serpin), due to a mutation (Met
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
358Arg
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
). One person with this mutation has been reported to have died of a lethal bleeding diathesis
Bleeding diathesis
In medicine , bleeding diathesis is an unusual susceptibility to bleeding mostly due to hypocoagulability, in turn caused by a coagulopathy . Several types are distinguished, ranging from mild to lethal...
.
Liver biopsy will show abundant PAS-positive globules within periportal hepatocytes.
Nomenclature
The protein was originally named "antitrypsin" because of its ability to covalently bind and irreversibly inactivate the enzyme trypsinTrypsin
Trypsin is a serine protease found in the digestive system of many vertebrates, where it hydrolyses proteins. Trypsin is produced in the pancreas as the inactive proenzyme trypsinogen. Trypsin cleaves peptide chains mainly at the carboxyl side of the amino acids lysine or arginine, except when...
in vitro. Trypsin, a type of peptidase, is a digestive enzyme active in the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
and elsewhere.
The term alpha-1 refers to the protein's behavior on protein electrophoresis
Protein electrophoresis
Protein electrophoresis is a method for analysing the proteins in a fluid or an extract. The electrophoresis may be performed with a small volume of sample in a number of alternative ways with or without a supporting medium: SDS polyacrylamide gel electrophoresis Protein electrophoresis is a method...
. On electrophoresis, the protein component of the blood is separated by electric current
Electric current
Electric current is a flow of electric charge through a medium.This charge is typically carried by moving electrons in a conductor such as wire...
. There are several clusters, the first being albumin
Serum albumin
Serum albumin, often referred to simply as albumin is a protein that in humans is encoded by the ALB gene.Serum albumin is the most abundant plasma protein in mammals. Albumin is essential for maintaining the osmotic pressure needed for proper distribution of body fluids between intravascular...
, the second being the alpha, the third beta and the fourth gamma (immunoglobulins). The non-albumin proteins are referred to as globulin
Globulin
Globulin is one of the three types of serum proteins, the others being albumin and fibrinogen. Some globulins are produced in the liver, while others are made by the immune system. The term globulin encompasses a heterogeneous group of proteins with typical high molecular weight, and both...
s.
The alpha region can be further divided into two sub-regions, termed "1" and "2". Alpha 1-antitrypsin is the main protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
of the alpha-globulin 1 region.
Another name used is alpha-1 proteinase inhibitor (α1-PI).
Genetics
The geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is located on the long arm of the fourteenth chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
(14q32.1).
Over 100 different variants of α1-antitrypsin have been described in various populations. North-Western Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
ans are most at risk for carrying one of the most common mutant forms of A1AT, the Z mutation (Glu342Lys on M1A, rs28929474).
Biochemical Properties
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-glycansGlycans
The term glycan refers to a polysaccharide or oligosaccharide. Glycans usually consist solely of O-glycosidic linkages of monosaccharides. For example, cellulose is a glycan composed of beta-1,4-linked D-glucose, and chitin is a glycan composed of beta-1,4-linked N-acetyl-D-glucosamine...
. However, one particular site shows a considerable amount of heterogeneity since tri- and even tetraantennary N-glycans
Glycans
The term glycan refers to a polysaccharide or oligosaccharide. Glycans usually consist solely of O-glycosidic linkages of monosaccharides. For example, cellulose is a glycan composed of beta-1,4-linked D-glucose, and chitin is a glycan composed of beta-1,4-linked N-acetyl-D-glucosamine...
can be attached to the Asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
107 (ExPASy amino acid nomenclature). These glycans
Glycans
The term glycan refers to a polysaccharide or oligosaccharide. Glycans usually consist solely of O-glycosidic linkages of monosaccharides. For example, cellulose is a glycan composed of beta-1,4-linked D-glucose, and chitin is a glycan composed of beta-1,4-linked N-acetyl-D-glucosamine...
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
Fucose
Fucose is a hexose deoxy sugar with the chemical formula C6H12O5. It is found on N-linked glycans on the mammalian, insect and plant cell surface, and is the fundamental sub-unit of the fucoidan polysaccharide...
as part of a so-called Sialyl Lewis x
Sialyl lewis x
Sialyl LewisX, also known as sialyl LeX and SLeX, is a tetrasaccharide carbohydrate that is usually attached to O-glycans on the surface of cells. It is known to play a vital role in cell-to-cell recognition processes. It is also the means in which an egg attracts sperm - first to stick to it,...
epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
, which could confer this protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
particular protein-cell recognition properties. The single cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residue of A1AT in position 256 (ExPASy
ExPASy
ExPASy is a bioinformatics resource portal operated by the Swiss Institute of Bioinformatics and in particular the SIB Web Team. It is an extensible and integrative portal accessing many scientific resources, databases and software tools in different areas of life sciences...
nomenclature) is found to be covalently linked to a free single cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
by a disulfide bridge.
Analysis
As proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
electrophoresis
Electrophoresis
Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
is imprecise, A1AT is analysed by isoelectric focusing
Isoelectric focusing
Isoelectric focusing , also known as electrofocusing, is a technique for separating different molecules by their electric charge differences...
(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
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
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
Alpha 1-antitrypsin deficiency
Alpha 1-antitrypsin deficiency is an autosomal recessive genetic disorder caused by defective production of alpha 1-antitrypsin , leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT protein in liver cells...
. 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
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
of the A1AT gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, 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
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
results, the IEF results are notated as in PiMM, where Pi stands for protease inhibitor
Protease inhibitor (biology)
In biology and biochemistry, protease inhibitors are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins....
and "MM" is the banding pattern of that patient.
Other detection methods include use of enzyme-linked-immuno-sorbent-assays in vitro and radial immunodiffusion.
Alpha 1-antitrypsin levels in the blood depend on the genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
, whereas others have a tendency to polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
ise, being retained in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
. 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 deficiencyAlpha 1-antitrypsin deficiencyAlpha 1-antitrypsin deficiency is an autosomal recessive genetic disorder caused by defective production of alpha 1-antitrypsin , leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT protein in liver cells...
)
- PiZ is caused by a glutamate to lysineLysineLysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
mutation at position 342 - PiS is caused by a glutamate to valineValineValine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
mutation at position 264
Other rarer forms have been described; in all there are over 80 variants.
Therapeutic use
RecombinantRecombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
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
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
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 augmention 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
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
. 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.
History
The possibility of allelicAllele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
variants of A1AT leading to disease was first investigated by Axelsson and Laurell
Carl-Bertil Laurell
Carl-Bertil Laurell was a Swedish medical doctor and researcher. Laurell was Professor of clinical chemistry at Lund University...
in 1965.
Further reading
- González-Sagrado M, López-Hernández S, Martín-Gil FJ, et al. (2000). "Alpha1-antitrypsin deficiencies masked by a clinical capillary electrophoresis system (CZE 2000)". Clinical Biochemistry, 33(1):79–80
Links
- The MEROPSMeropsMerops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
online database for peptidases and their inhibitors: I04.001 - Proteopedia: Alpha-1-antitrypsin