Heparin antagonists are potent inhibitors of mast cell tryptase

Abstract

Tryptase may be a key mediator in mast cell-mediated inflammatory reactions. When mast cells are activated, they release large amounts of these tetrameric trypsin-like serine proteases. Tryptase is present in a macromolecular complex with heparin proteoglycan where the interaction with heparin is known to be essential for maintaining enzymatic activity. Recent investigations have shown that tryptase has potent proinflammatory activity, and inhibitors of tryptase have been shown to modulate allergic reactions in vivo. Many of the tryptase inhibitors investigated previously are directed against the active site. In the present study we have investigated an alternative approach for tryptase regulation. We show that the heparin antagonists Polybrene and protamine are potent inhibitors of both human lung tryptase and of recombinant mouse tryptase (mouse mast cell protease 6). Protamine inhibited tryptase in a competitive manner whereas Polybrene showed noncompetitive inhibition kinetics. Treatment of tetrameric, active tryptase with Polybrene caused dissociation into monomers, accompanied by complete loss of enzymatic activity. The present report thus suggests that heparin antagonists potentially may be used in treatment of mast cell-mediated diseases such as asthma.

Published in

Biochemistry
2001, volume: 40, number: 24, pages: 7342-7349
Publisher: AMER CHEMICAL SOC

SLU Authors

• Hallgren, Jenny

  • Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences
    

• Estrada, Sergio

  • Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences
    

• Pejler, Gunnar

  • Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences
    

Associated SLU-program

Future Animal Health and Welfare (until Jan 2017)

UKÄ Subject classification

Biochemistry
Molecular Biology

Publication identifier

• DOI: https://doi.org/10.1021/bi001988c

Permanent link to this page (URI)

https://res.slu.se/id/publ/66608