alpha-1-antitrypsin; alpha-1 protease inhibitor; alpha-1-antiproteinase; Serpin A1 (SERPINA1, AAT, PI, PRO0684, PRO2209)
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Function
- inhibitor of serine proteases
- constitutes 90% of serum antitrypsin activity although relatively inactive towards trypsin
- its main function is to inactivate lysosomal elastase released upon phagocytosis of particles by neutrophils
- moderate affinity for plasmin & thrombin
- rreversibly inhibits trypsin, chymotrypsin & plasminogen activator
- it passes through capillary walls
- alpha-1 antitrypsin normally accounts for 70% of alpha-1 band on serum protein electrophoresis
- short peptide from AAT (SPAAT)
- reversible chymotrypsin inhibitor
- also inhibits elastase
- does not inhibit trypsin
- major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human eukocyte elastase (HLE) proteolytic processing may yield the truncated form that ranges from Asp-30 to Lys-418
Structure
- N-glycosylated
- differential glycosylation produces a number of isoforms
- N-linked glycan at Asn-107 is alternatively di-antennary, tri-antennary or tetra-antennary
- the glycan at Asn-70 is di-antennary with trace amounts of tri-antennary
- glycan at Asn-271 is exclusively di-antennary
- structure of glycans at Asn- 70 & Asn-271 is hex5hexNAc4
- the structure of the antennae is neu5Ac(alpha1-6)gal(beta1-4)GlcNAc attached to the core man(alpha1-6)[man(alpha1-3)]man(beta1-4)GlcNAc(beta1-4)GlcNAc
- some antennae are fucosylated, which forms a Lewis-X determinant
- the reactive center loop (RCL) extends out from the body of the protein & directs binding to the target protease
- the protease cleaves the serpin at the reactive site within the RCL, establishing a covalent linkage between the carboxyl group of the serpin reactive site & the Ser hydroxyl of the protease
- resulting inactive serpin-protease complex is highly stable
- belongs to the serpin family
Compartment
- secreted, extracellular space, extracellular matrix
- short peptide from AAT (SPAAT): secreted,
Alternative splicing
- named isoforms=3
- at least one isoforms may be expressed at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay
Expression
Pathology
- defects in SERPINA1 are the cause of alpha-1-antitrypsin deficiency
- an aberrant form is found in the plasma of chronic smokers
- persists after smoking is ceased
- can still be found 10 years after smoking has ceased
- inhibits insulin-induced NO synthesis in platelets
- decreases coagulation time
- has proteolytic activity against insulin & plasmin
Polymorphism
- M1V 44-49% (most common allele)
- M1A 20-23%
- M2 10=11%;
- M3 14-19%
Pharmacology
Available only through specialty pharmacies
Tradename: Prolastin, Zemaira, Aralast
Indications
alpha-1 antitrypsin deficiency
Dosage
- 60 mg/kg IV once weekly
Injection: > 20 mg alpha-1 antitrypsin/mL (vials 500 & 1000 mg)
Adverse effects
- uncommon (< 1%)
- dizziness, lightheadedness, leukocytosis, fever (< 102 F) delayed 12 hours after treatment
More general terms
- acute phase protein
- alpha 1 globulin
- serine protease inhibitor; serpin
- glycoprotein
- metabolic agent (metabolic modifier)
More specific terms
Additional terms
References
- ↑ Fundamentals of Clinical Chemistry 3rd ed., N.W. Teitz ed., W.B. Saunders, 1988, pg 330
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Prescriber's Letter 11(2):suppl 2004
- ↑ UniProt http://www.uniprot.org/uniprot/P01009.html
- ↑ GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/SERPINA1
- ↑ Wikipedia; Note: alpha-1 antitrypsin entry http://en.wikipedia.org/wiki/alpha_1-antitrypsin