Synthesis in E. coli of α1-antitrypsin variants of therapeutic potential for emphysema and thrombosis

Michael Courtney, Sophie Jallat, Luc Henri Tessier, Annie Benavente, Ronald Crystal, Jean Pierre Lecocq

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

The primary function of α1-antitrypsin (α1-AT), an antiprotease produced by the liver, is the inhibition of neutrophil elastase, a protease capable of hydrolysing most connective tissue components1-4. The importance of α1-AT is demonstrated by the high incidence of early-onset emphysema in individuals with hereditary α1-AT deficiency (Type PiZZ), in whom serum levels of α1-AT are 10-20% of normal 5-10. Oxidants in tobacco smoke can inactivate α1-AT in vitro11,12, and studies have shown that α1-AT from the lungs of individuals who smoke cigarettes may also be partially inactivated, perhaps explaining the high incidence of emphysema associated with cigarette smoking13,14. Oxidative inactivation is probably due to modification of the Met residue (Met358) at the P1 subsite position of the elastase binding site of the protein15,16. To study the possibility of modulating the biological properties of α1-AT, we have introduced selected sequence modifications at the reactive site by in vitro mutation of a cloned α1-AT complementary DNA. We describe here the characterization of two α1-AT analogues produced in Escherichia coli. The first, α1-AT(Met385→Val), is not only fully active as an elastase inhibitor but is also resistant to oxidative inactivation. The other, α1-AT(Met 358→Arg), no longer inhibits elastase but is an efficient thrombin inhibitor. The active site of the latter is identical to that of the α1-AT (Pittsburgh) variant, which was associated with a fatal bleeding disorder17,18.

Original languageEnglish
Pages (from-to)149-151
Number of pages3
JournalNature
Volume313
Issue number5998
DOIs
Publication statusPublished - 1 Dec 1985
Externally publishedYes

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Pancreatic Elastase
Emphysema
Thrombosis
Escherichia coli
Smoke
Tobacco Products
Catalytic Domain
Leukocyte Elastase
Incidence
Protease Inhibitors
Oxidants
Thrombin
Connective Tissue
Tobacco
Peptide Hydrolases
Therapeutics
Complementary DNA
Binding Sites
Hemorrhage
Lung

ASJC Scopus subject areas

  • General

Cite this

Courtney, M., Jallat, S., Tessier, L. H., Benavente, A., Crystal, R., & Lecocq, J. P. (1985). Synthesis in E. coli of α1-antitrypsin variants of therapeutic potential for emphysema and thrombosis. Nature, 313(5998), 149-151. https://doi.org/10.1038/313149a0

Synthesis in E. coli of α1-antitrypsin variants of therapeutic potential for emphysema and thrombosis. / Courtney, Michael; Jallat, Sophie; Tessier, Luc Henri; Benavente, Annie; Crystal, Ronald; Lecocq, Jean Pierre.

In: Nature, Vol. 313, No. 5998, 01.12.1985, p. 149-151.

Research output: Contribution to journalArticle

Courtney, M, Jallat, S, Tessier, LH, Benavente, A, Crystal, R & Lecocq, JP 1985, 'Synthesis in E. coli of α1-antitrypsin variants of therapeutic potential for emphysema and thrombosis', Nature, vol. 313, no. 5998, pp. 149-151. https://doi.org/10.1038/313149a0
Courtney, Michael ; Jallat, Sophie ; Tessier, Luc Henri ; Benavente, Annie ; Crystal, Ronald ; Lecocq, Jean Pierre. / Synthesis in E. coli of α1-antitrypsin variants of therapeutic potential for emphysema and thrombosis. In: Nature. 1985 ; Vol. 313, No. 5998. pp. 149-151.
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