PMID: 9636142Jun 24, 1998Paper

alpha1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent

Proceedings of the National Academy of Sciences of the United States of America
F JeanG Thomas

Abstract

The important role of furin in the proteolytic activation of many pathogenic molecules has made this endoprotease a target for the development of potent and selective antiproteolytic agents. Here, we demonstrate the utility of the protein-based inhibitor alpha1-antitrypsin Portland (alpha1-PDX) as an antipathogenic agent that can be used prophylactically to block furin-dependent cell killing by Pseudomonas exotoxin A. Biochemical analysis of the specificity of a bacterially expressed His- and FLAG-tagged alpha1-PDX (alpha1-PDX/hf) revealed the selectivity of the alpha1-PDX/hf reactive site loop for furin (Ki, 600 pM) but not for other proprotein convertase family members or other unrelated endoproteases. Kinetic studies show that alpha1-PDX/hf inhibits furin by a slow tight-binding mechanism characteristic of serpin molecules and functions as a suicide substrate inhibitor. Once bound to furin's active site, alpha1-PDX/hf partitions with equal probability to undergo proteolysis by furin at the C-terminal side of the reactive center -Arg355-Ile-Pro-Arg358- downward arrow or to form a kinetically trapped SDS-stable complex with the enzyme. This partitioning between the complex-forming and proteolytic pathways contributes to the ab...Continue Reading

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Citations

Oct 4, 2000·Journal of Peptide Science : an Official Publication of the European Peptide Society·J Deadman
Sep 1, 2005·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Abdel-Majid KhatibL'Houcine Ouafik
Oct 11, 2005·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Ajoy Basak
Mar 14, 2007·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Nabil G Seidah, Annik Prat
Apr 23, 2004·Trends in Biochemical Sciences·Nathan C Rockwell, Jeremy W Thorner
Dec 30, 2009·Journal of Medicinal Chemistry·Gero L BeckerTorsten Steinmetzer
Oct 3, 2002·Nature Reviews. Molecular Cell Biology·Gary Thomas
Dec 30, 2011·The New England Journal of Medicine·Andrew W Artenstein, Steven M Opal
Aug 5, 2009·The Journal of Biological Chemistry·Sylvia M Nelsen, Jan L Christian
Apr 14, 2010·The Journal of Biological Chemistry·Sharron A N BrownJeffrey A Winkles
Jan 21, 2011·The Journal of Biological Chemistry·Ralf M LeonhardtPeter Cresswell
Apr 28, 2012·The Journal of Biological Chemistry·Gero L BeckerTorsten Steinmetzer
Apr 1, 2009·The Journal of Biological Chemistry·Tomoko KomiyamaRobert S Fuller
Dec 6, 2007·The Journal of Infectious Diseases·Ute StröherHeinz Feldmann
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Mar 17, 2010·BMC Cell Biology·Jenny E FelinLaura C Bridgewater
Oct 29, 2010·Journal of Cell Science·Sylvain M Le GallCarl P Blobel

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