Inhibition of Neutrophil Cathepsin G by Oxidized Mucus Proteinase Inhibitor. Effect of Heparin † - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Biochemistry Année : 1999

Inhibition of Neutrophil Cathepsin G by Oxidized Mucus Proteinase Inhibitor. Effect of Heparin †

Résumé

Oxidation of mucus proteinase inhibitor (MPI) transforms Met73, the P'1 residue of its active center into methionine sulfoxide and lowers its affinity for neutrophil elastase [Boudier, C., and Bieth, J. G. (1994) Biochem. J. 303, 61-68]. Here, we show that the oxidized inhibitor has also a decreased affinity for neutrophil cathepsin G and pancreatic chymotrypsin. The Ki of the oxidized MPI-cathepsin G complex (1.2 microM) is probably too high to be compatible with significant inhibition of cathepsin G in inflammatory lung secretions. Stopped-flow kinetics shows that, within the inhibitor concentration range used, the mechanism of inhibition of cathepsin G and chymotrypsin by oxidized MPI is consistent with a one-step reaction, [equation in text] whereas the inhibition of elastase takes place in two steps, [equation in text]. Heparin, which accelerates the inhibition of the three proteinases by native MPI, also favors their interaction with oxidized MPI. Flow calorimetry shows that heparin binds oxidized MPI with Kd, Delta H degrees, and Delta S degrees values close to those reported for native MPI. In the presence of heparin, oxidized MPI inhibits cathepsin G via a two-step reaction characterized by Ki = 0.22 microM, k2 = 0.1 s-1, k-2 = 0.023 s-1, and Ki = 42 nM. Under these conditions, in vivo inhibition of cathepsin G is again possible. Heparin also improves the inhibition of chymotrypsin and elastase by oxidized MPI by increasing their kass or k2/Ki and decreasing their Ki. Our data suggest that oxidation of MPI during chronic bronchitis may lead to cathepsin G-mediated lung tissue degradation and that heparin may be a useful adjuvant of MPI-based therapy of acute lung inflammation in cystic fibrosis.

Dates et versions

hal-02150373 , version 1 (07-06-2019)

Identifiants

Citer

C Boudier, Martine Cadène, Joseph Bieth. Inhibition of Neutrophil Cathepsin G by Oxidized Mucus Proteinase Inhibitor. Effect of Heparin †. Biochemistry, 1999, 38 (26), pp.8451-8457. ⟨10.1021/bi9828526⟩. ⟨hal-02150373⟩

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