Interactions of Human Matrix Metalloproteinase 7(Matrilysin) with the Inhibitors Thiorphan and R-94138.

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  • Oneda Hiroshi
    Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University
  • Inouye Kuniyo
    Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University

書誌事項

公開日
2001
資源種別
journal article
DOI
  • 10.1093/oxfordjournals.jbchem.a002874
公開者
社団法人 日本生化学会

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説明

The effects of the metalloproteinase inhibitors thiorphan and R-94138 on the matrilysincatalyzed hydrolysis of (7-methoxycoumarin-4-yl)acetyl-L-Pro-L-Leu-Gly-L-Leu-[N3-(2, 4-dinitrophenyl)-L-2, 3-diamino-propionyl]-L-Ala-L-Arg-NH2 [MOCAc-PLGL(Dpa)AR] were examined. The inhibitor constants (Ki) of thiorphan and R-94138 for matrilysin at pH 7.5, 25°C were determined to be 11.2 and 7.65μM, respectively. From the temperature dependence of the Ki values at pH 7.5, the standard enthalpy change (ΔH°) values for the binding of matrilysin with thiorphan and R-94138 were determined to be -(18.2±0.9) and (1.65±1.07) kJ•mol-1, respectively. The binding of matrilysin to thiorphan is exothermic and the free energy change in the complex formation depends mainly on the change in enthalpy, while the binding to R-94138 is endothermic and typically entropy-driven. Hydrophobic interactions are suggested to contribute significantly to the binding of matrilysin to R-94138 as well as to the substrate. The pH dependence of the Ki value suggests that at least two ionizing groups with pKa values of 4.5 and 9.1-9.3 are involved in the binding. The matrilysin activity is regulated by ionizing groups with pKa values of 4.3 and 9.6. Both inhibition and hydrolysis are suggested to be controlled by the same residues in matrilysin, most likely Glu 198 and Tyr 219, respectively.

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