Mechanistic studies on the inhibition of stromelysin by a peptide phosphonamidate

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Abstract

We have investigated the inhibition of the human matrix metalloproteinase stromelysin (SLN) by the peptide phosphonamidate, phthaloyl-N-(CH2)4-P(O2--Ile -(β-naphthyl)Ala-NH-CH3, and find that it is a potent, slow-binding inhibitor of SLN with kon = 2.7 × 104 M-1 sec-1, koff = 1.9 x 10-4 sec-1, and Ki = 7 nM (pH 5.0, 25°C). To probe the mechanism of inhibition, we determined pH-dependencies and solvent deuterium isotope effects. pH-dependencies of the kinetic parameters for inhibition are complex but reflect greater inhibitory potency at lower pH and suggest a mechanism for inhibition that involves the same active site groups as are involved in catalysis. The solvent isotope on kon (kon,H2O/kon,D2O) is normal and equals 1.5 ± 0.1. Together with the pH-dependence of inhibition, this value suggests that kon is rate-limited by a process that involves general-acid/general-base catalysis. We propose that kon is rate-limited by general-acid catalyzed ligand exchange of inhibitor for the zinc-bound water molecule. © 1993.

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Izquierdo-Martin, M., & Ross L., S. (1993). Mechanistic studies on the inhibition of stromelysin by a peptide phosphonamidate. Bioorganic and Medicinal Chemistry, 1(1), 19–26. https://doi.org/10.1016/S0968-0896(00)82099-4

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