Document Detail


Synthesis in yeast of a functional oxidation-resistant mutant of human alpha-antitrypsin.
MedLine Citation:
PMID:  6387509     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cumulative damage to lung tissue by leukocyte elastase is thought to be responsible for the development of pulmonary emphysema, an irreversible lung disease characterized by loss of lung elasticity. It is also thought to be involved in the rapidly developing and usually fatal adult respiratory distress syndrome. The primary defence against elastase damage is the anti-protease known as alpha 1-antitrypsin, a glycosylated serum protein of 394 amino acids. Oxidation of the methionine 358 residue located at the active centre of alpha 1-antitrypsin results in a dramatic decrease in inhibitory activity towards elastase which effectively inactivates the protective function. It has been suggested that this oxidation sensitivity has a regulatory function and allows tissue breakdown at sites of inflammation by inactivation of alpha 1-antitrypsin by oxygen radicals released by phagocytes. In the above diseases, however, the oxidative inactivation of alpha 1-antitrypsin is probably of major importance in allowing lung damage by elastase. An oxidation-resistant alpha 1-antitrypsin required for emphysemics and provide treatment for acute inflammatory respiratory conditions. To further the possibility of therapy for the above conditions, we describe here the synthesis in yeast of active, non-glycosylated, human alpha 1-antitrypsin. Site-directed mutagenesis has been used to construct an active, oxidation-resistant derivative containing a single methionine to valine substitution at the active centre. This demonstrates the potential of engineered modifications to protein molecules designed to improve their physiological function.
Authors:
S Rosenberg; P J Barr; R C Najarian; R A Hallewell
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Nature     Volume:  312     ISSN:  0028-0836     ISO Abbreviation:  Nature     Publication Date:    1984 Nov 1-7
Date Detail:
Created Date:  1984-12-06     Completed Date:  1984-12-06     Revised Date:  2006-05-01    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  77-80     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
GENBANK/V00496;  X01683
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Base Sequence
Cloning, Molecular*
DNA / metabolism
Genes*
Humans
Molecular Weight
Mutation*
Oxidation-Reduction
Plasmids
Saccharomyces cerevisiae / genetics*
alpha 1-Antitrypsin / genetics*,  isolation & purification,  metabolism
Chemical
Reg. No./Substance:
0/alpha 1-Antitrypsin; 9007-49-2/DNA

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


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