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alpha-1-antitrypsin; alpha-1 protease inhibitor; alpha-1-antiproteinase; Serpin A1 (SERPINA1, AAT, PI, PRO0684, PRO2209)

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: plasma Polymorphism: - M1V 44-49% (most common allele) - M1A 20-23% - M2 10=11%; - M3 14-19% 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 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

Related

alpha-1 antitrypsin deficiency alpha-1 antitrypsin in serum/plasma (AAT)

Specific

Alpha 1 Antitrypsin Parenteral

General

acute phase protein alpha 1 globulin glycoprotein metabolic agent (metabolic modifier) serine protease inhibitor; serpin

Properties

SIZE: entity length = 418 aa MW = 47 kD COMPARTMENT: plasma MOTIF: signal sequence {1-24} N-glycosylation site {N70} N-glycosylation site {N107} N-glycosylation site {N271} RCL {368-392} MOTIF: peptide motif {382-383} INHIBITS: elastase MISC-INFO: CONCENTRATION 200-400 MG/DL

Database Correlations

OMIM correlations UniProt P01009 Pfam PF00079 Entrez Gene 5265 Kegg hsa:5265

References

  1. Fundamentals of Clinical Chemistry 3rd ed., N.W. Teitz ed., W.B. Saunders, 1988, pg 330
  2. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  3. Prescriber's Letter 11(2):suppl 2004
  4. UniProt :accession P01009
  5. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/SERPINA1
  6. Wikipedia; Note: alpha-1 antitrypsin entry http://en.wikipedia.org/wiki/alpha_1-antitrypsin