, Volume 17, Issue 6, pp 853-860
Date: 22 May 2012

Kinetics and thermodynamics of irreversible inhibition of matrix metalloproteinase 2 by a Co(III) Schiff base complex

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Abstract

Cobalt(III) Schiff base complexes have been used as potent inhibitors of protein function through the coordination to histidine residues essential for activity. The kinetics and thermodynamics of the binding mechanism of Co(acacen)(NH3)2Cl [Co(acacen); where H2acacen is bis(acetylacetone)ethylenediimine] enzyme inhibition has been examined through the inactivation of matrix metalloproteinase 2 (MMP-2) protease activity. Co(acacen) is an irreversible inhibitor that exhibits time- and concentration-dependent inactivation of MMP-2. Co(acacen) inhibition of MMP-2 is temperature-dependent, with the inactivation increasing with temperature. Examination of the formation of the transition state for the MMP-2/Co(acacen) complex was determined to have a positive entropy component indicative of greater disorder in the MMP-2/Co(acacen) complex than in the reactants. With further insight into the mechanism of Co(acacen) complexes, Co(III) Schiff base complex protein inactivators can be designed to include features regulating activity and protein specificity. This approach is widely applicable to protein targets that have been identified to have clinical significance, including matrix metalloproteinases. The mechanistic information elucidated here further emphasizes the versatility and utility of Co(III) Schiff base complexes as customizable protein inhibitors.

Graphical abstract

Irreversible inhibition of matrix metalloproteinase 2 (MMP-2) protease activity by the Co(III) Schiff base complex [Co(acacen)(NH3)2Cl] is dependent on time and concentration. The slow inhibition is temperature-dependent, with inhibition increasing with temperature. The positive entropy observed is likely a result of deformation of the protein secondary structure upon Co(acacen)(NH3)2Cl binding.