Heparin accelerates the inhibition of cathepsin G by mucus proteinase inhibitor: potent effect of O-butyrylated heparin
Mechanism study published in Biochemical Journal (1998)
Abstract
Heparin tightly binds cathepsin G and so protects the enzyme from inhibition by alpha1-antichymotrypsin, alpha1-proteinase inhibitor and eglin c, three proteins which do not bind heparin [Ermolieff J., Boudier C., Laine A., Meyer B. and Bieth J.G. (1994) J. Biol. Chem. 269, 29502-29508]. Here we show that heparin no longer protects cathepsin G from inhibition when the enzyme is reacted with mucus proteinase inhibitor (MPI), a heparin-binding protein. Heparin fragments of Mr=4500 and 8100 and O-butyrylated heparin of Mr=8000 form tight complexes with cathepsin G (Kd=0.5-2.2 nM) and MPI (Kd=0. 4-0.8 muM) and accelerate the MPI-promoted inhibition of cathepsin G by a factor of 17-26. They also accelerate the inhibition of neutrophil elastase and pancreatic chymotrypsin. The rate acceleration is due to the binding of heparin to MPI. Butyrylation of heparin slightly decreases its affinity for cathepsin G and MPI but sharply decreases the ionic interactions between the positively charged proteins and the negatively charged polyanion. The butyrylated heparin derivative is the best rate accelerator: it increases the rate constant for the MPI-induced inhibition of cathepsin G and elastase by factors of 26 and 23, respectively. This, together with the fact that it has a good bioavailability and a very low anticoagulant activity, suggests that it might be an adjuvant of MPI-based therapy of cystic fibrosis.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Summary
Mechanistic study showing heparin enhances mucus protease inhibitor activity against cathepsin G — relevant scaffold for leech-eglin–like inhibitor engineering.
Why This Matters for Hirudotherapy
This in-vitro study examined how heparin and O-butyrylated heparin fragments accelerate the inhibition of cathepsin G by mucus proteinase inhibitor (MPI), finding 17–26-fold rate enhancements and showing that butyrylated heparin was the most effective accelerator while possessing low anticoagulant activity and good bioavailability. The authors suggest butyrylated heparin may be useful as an adjuvant in MPI-based therapy for cystic fibrosis. The abstract references eglin c only as one of three proteins whose inhibition of cathepsin G is blocked by heparin, based on prior work by other authors, without further characterizing it. This study does not investigate leeches, hirudotherapy, or leech-derived agents as its subject, and its relevance to ASH's core domain is marginal at best, as no leech connection is addressed in this abstract.
Citation
Heparin accelerates the inhibition of cathepsin G by mucus proteinase inhibitor: potent effect of O-butyrylated heparin.
Ermolieff J et al. · The Biochemical journal, 1998
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