Synthesis in yeast of a functional oxidation-resistant mutant of human α1-antitrypsin View Full Text


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Article Info

DATE

1984-11

AUTHORS

Steven Rosenberg, Philip J. Barr, Richard C. Najarian, Robert A. Hallewell

ABSTRACT

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. More... »

PAGES

77-80

Journal

TITLE

Nature

ISSUE

5989

VOLUME

312

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/312077a0

    DOI

    http://dx.doi.org/10.1038/312077a0

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1024320128

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/6387509


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    55 schema:description 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.
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