Mechanistic studies on the inhibition of stromelysin by a peptide phosphonamidate

  • Izquierdo-Martin M
  • Ross L. S
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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 × 104M-1sec-1, koff= 1.9 x 10-4sec-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 konis rate-limited by a process that involves general-acid/general-base catalysis. We propose that konis rate-limited by general-acid catalyzed ligand exchange of inhibitor for the zinc-bound water molecule. © 1993.

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Authors

  • Maria Izquierdo-Martin

  • Stein Ross L.

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