Document Detail


Altered specificities of genetically engineered alpha 1 antitrypsin variants.
MedLine Citation:
PMID:  3509863     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Seven active site variants of human alpha 1-antitrypsin (alpha 1AT) were produced in Escherichia coli following site-specific mutagenesis of the alpha 1AT complementary DNA. alpha 1AT (Ala358), alpha 1AT (Ile358) and alpha 1AT (Val358) were efficient inhibitors of both neutrophil and pancreatic elastases, but not of cathepsin G. alpha 1AT (Ala356, Val358) and alpha 1AT (Phe358) specifically inhibited pancreatic elastase and cathepsin G respectively. The most potent inhibitor of neutrophil elastase was alpha 1AT (Leu358), which also proved to be effective against cathepsin G. The alpha 1AT (Arg358) variant inactivated thrombin with kinetics similar to antithrombin III in the presence of heparin. Electrophoretic analysis showed that SDS-stable high mol. wt complexes were formed between the mutant inhibitors and the cognate proteases in each case. These data indicate that effective inhibition occurs when the alpha 1AT P1 residue (position 358) corresponds to the primary specificity of the target protease. Moreover, alteration of the P3 residue (position 356) can further modify the reactivity of the inhibitor. Two of the variants have therapeutic potential: alpha 1AT (Leu358) may be more useful than plasma alpha 1AT in the treatment of destructive lung disorders and alpha 1AT (Arg358) could be effective in the control of thrombosis.
Authors:
S Jallat; D Carvallo; L H Tessier; D Roecklin; C Roitsch; F Ogushi; R G Crystal; M Courtney
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Protein engineering     Volume:  1     ISSN:  0269-2139     ISO Abbreviation:  Protein Eng.     Publication Date:    1986 Oct-Nov
Date Detail:
Created Date:  1989-05-11     Completed Date:  1989-05-11     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8801484     Medline TA:  Protein Eng     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  29-35     Citation Subset:  IM    
Affiliation:
Department of Molecular Biology, Transgene S.A., Strasbourg, France.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Base Sequence
Binding Sites
Cathepsin G
Cathepsins / antagonists & inhibitors
Genetic Variation
Humans
Molecular Sequence Data
Pancreatic Elastase / antagonists & inhibitors
Protein Engineering
Serine Endopeptidases
Thrombin / antagonists & inhibitors
alpha 1-Antitrypsin / genetics*,  pharmacology
Chemical
Reg. No./Substance:
0/alpha 1-Antitrypsin; EC 3.4.-/Cathepsins; EC 3.4.21.-/Serine Endopeptidases; EC 3.4.21.20/CTSG protein, human; EC 3.4.21.20/Cathepsin G; EC 3.4.21.36/Pancreatic Elastase; EC 3.4.21.5/Thrombin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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