Kinetics and thermodynamics of irreversible inhibition of matrix metalloproteinase 2 by a Co(III) Schiff base complex.
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)(NH(3))(2)Cl [Co(acacen); where H(2)acacen 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.
Department of Chemistry, Northwestern University, Evanston, IL 60208, USA. a-harney@northwestern.edu
Allison S
AS
Harney
Laura B
LB
Sole
Thomas J
TJ
Meade
D003035:Cobalt / Q000737:chemistry* / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012545:Schiff Bases / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013696:Temperature; D013816:Thermodynamics; D013997:Time Factors
D056831:Coordination Complexes; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D012545:Schiff Bases; D003035:Cobalt; D020778:Matrix Metalloproteinase 2