JBIC Journal of Biological Inorganic Chemistry

, Volume 17, Issue 6, pp 853–860 | Cite as

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

  • Allison S. Harney
  • Laura B. Sole
  • Thomas J. Meade
Original Paper

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.

Keywords

Protein inhibition Histidine Matrix metalloproteinase Cobalt 

Supplementary material

775_2012_902_MOESM1_ESM.doc (1 mb)
Supplementary material 1 (DOC 1027 kb)

References

  1. 1.
    Bruijnincx PC, Sadler PJ (2008) New trends for metal complexes with anticancer activity. Curr Opin Chem Biol 12(2):197–206PubMedCrossRefGoogle Scholar
  2. 2.
    Louie AY, Meade TJ (1998) A cobalt complex that selectively disrupts the structure and function of zinc fingers. Proc Natl Acad Sci USA 95(12):6663–6668PubMedCrossRefGoogle Scholar
  3. 3.
    Boettcher A, Takeuchi T, Hardcastle K, Meade TJ, Gray HB (1997) Spectroscopy and electrochemistry of Cobalt(III) Schiff base complexes. Inorg Chem 36:2498–2504CrossRefGoogle Scholar
  4. 4.
    Takeuchi T, Bottcher A, Quezada CM, Meade TJ, Gray HB (1999) Inhibition of thermolysin and human alpha-thrombin by cobalt(III) Schiff base complexes. Bioorg Med Chem 7(5):815–819PubMedCrossRefGoogle Scholar
  5. 5.
    Blum O, Haiek A, Cwikel D, Dori Z, Meade TJ, Gray HB (1998) Isolation of a myoglobin molten globule by selective Cobalt(III)-induced unfolding. Proc Natl Acad Sci USA 95(12):6659–6662PubMedCrossRefGoogle Scholar
  6. 6.
    Harney AS, Lee J, Manus LM, Wang P, Ballweg DM, LaBonne C, Meade TJ (2009) Targeted inhibition of Snail family zinc finger transcription factors by oligonucleotide–Co(III) Schiff base conjugate. Proc Nat Acad Sci USA 106(33):13667–13672PubMedCrossRefGoogle Scholar
  7. 7.
    Harney AS, Meade TJ, Labonne C (2012) Targeted inactivation of Snail family EMT regulatory factors by a Co(III)-Ebox conjugate. PLoS ONE 7(2):e32318PubMedCrossRefGoogle Scholar
  8. 8.
    Hurtado RR, Harney AS, Heffern MC, Holbrook RJ, Holmgren RA, Meade TJ (2012) Specific inhibition of the transcription factor Ci by a cobalt(III) Schiff base–DNA conjugate. Mol Pharm 9(2):325–333PubMedCrossRefGoogle Scholar
  9. 9.
    Takeuchi T, Boettcher A, Quezada CM, Simon MI, Meade TJ, Gray HB (1998) Selective inhibition of human α-thrombin by Cobalt(III) Schiff base complexes. J Am Chem Soc 120(33):8555–8556CrossRefGoogle Scholar
  10. 10.
    Ortega N, Wang K, Ferrara N, Werb Z, Vu TH (2010) Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation. Dis Model Mech 3(3–4):224–235PubMedCrossRefGoogle Scholar
  11. 11.
    Kiran MS, Viji RI, Kumar SV, Prabhakaran AA, Sudhakaran PR (2011) Changes in expression of VE-cadherin and MMPs in endothelial cells: Implications for angiogenesis. Vasc Cell 3(1):6PubMedCrossRefGoogle Scholar
  12. 12.
    Morancho A, Rosell A, Garcia-Bonilla L, Montaner J (2010) Metalloproteinase and stroke infarct size: role for anti-inflammatory treatment? Ann N Y Acad Sci 1207:123–133PubMedCrossRefGoogle Scholar
  13. 13.
    Hansson J, Vasan RS, Arnlov J, Ingelsson E, Lind L, Larsson A, Michaelsson K, Sundstrom J (2011) Biomarkers of extracellular matrix metabolism (MMP-9 and TIMP-1) and risk of stroke, myocardial infarction, and cause-specific mortality: cohort study. PLoS ONE 6(1):e16185PubMedCrossRefGoogle Scholar
  14. 14.
    Wernicke D, Seyfert C, Gromnica-Ihle E, Stiehl P (2006) The expression of collagenase 3 (MMP-13) mRNA in the synovial tissue is associated with histopathologic type II synovitis in rheumatoid arthritis. Autoimmunity 39(4):307–313PubMedCrossRefGoogle Scholar
  15. 15.
    Jezierska A, Motyl T (2009) Matrix metalloproteinase-2 involvement in breast cancer progression: a mini-review. Med Sci Monit 15(2):RA32–40Google Scholar
  16. 16.
    Diaz N, Suarez D (2007) Molecular dynamics simulations of matrix metalloproteinase 2: role of the structural metal ions. Biochemistry 46(31):8943–8952PubMedCrossRefGoogle Scholar
  17. 17.
    Kleifeld O, Kotra LP, Gervasi DC, Brown S, Bernardo MM, Fridman R, Mobashery S, Sagi I (2001) X-ray absorption studies of human matrix metalloproteinase-2 (MMP-2) bound to a highly selective mechanism-based inhibitor. J Biol Chem 276(20):17125–17131PubMedCrossRefGoogle Scholar
  18. 18.
    Costa G, Mestroni G, Tauzher G, Stefani L (1966) Organometallic derivatives of cobalt chelates of bis(acetylacetone) ethylendiamine. J Organomet Chem 6(2):181–187CrossRefGoogle Scholar
  19. 19.
    Kitz R, Wilson IB (1962) Esters of methanesulfonic acid as irreversible inhibitors of acetylcholinesterase. J Biol Chem 237:3245–3249PubMedGoogle Scholar
  20. 20.
    Segel IH (1975) Enzyme kinetics: behavior and analysis of rapid equilibrium and steady-state enzyme systems. Wiley, New YorkGoogle Scholar
  21. 21.
    Copeland RA (2005) Evaluation of enzyme inhibitors in drug discovery. A guide for medicinal chemists and pharmacologists. Methods Biochem Anal 46:1–265PubMedGoogle Scholar
  22. 22.
    Laidler KJ, Meiser JH (1982) Physical chemistry. Benjamin/Cummings, Menlo ParkGoogle Scholar
  23. 23.
    Bode W, Gomis-Rueth F-X, Stoeckler W (1993) Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the ‘metzincins’. FEBS Lett 331(1–2):134–140PubMedCrossRefGoogle Scholar
  24. 24.
    Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92(8):827–839PubMedCrossRefGoogle Scholar
  25. 25.
    Jacobsen JA, Major Jourden JL, Miller MT, Cohen SM (2010) To bind zinc or not to bind zinc: an examination of innovative approaches to improved metalloproteinase inhibition. Biochim Biophys Acta Mol Cell Res 1803(1):72–94Google Scholar
  26. 26.
    Overall CM, Kleifeld O (2006) Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 6(3):227–239PubMedCrossRefGoogle Scholar
  27. 27.
    Brown S, Bernardo MM, Li Z-H, Kotra LP, Tanaka Y, Fridman R, Mobashery S (2000) Potent and selective mechanism-based inhibition of gelatinases. J Am Chem Soc 122(28):6799–6800CrossRefGoogle Scholar
  28. 28.
    Ikejiri M, Bernardo MM, Bonfil RD, Toth M, Chang M, Fridman R, Mobashery S (2005) Potent mechanism-based inhibitors for matrix metalloproteinases. J Biol Chem 280(40):33992–34002PubMedCrossRefGoogle Scholar
  29. 29.
    Johnson AR, Pavlovsky AG, Ortwine DF, Prior F, Man C-F, Bornemeier DA, Banotai CA, Mueller WT, McConnell P, Yan C et al (2007) Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects. J Biol Chem 282(38):27781–27791PubMedCrossRefGoogle Scholar
  30. 30.
    Hurwitz MD (2010) Today’s thermal therapy: not your father’s hyperthermia: challenges and opportunities in application of hyperthermia for the 21st century cancer patient. Am J Clin Oncol 33(1):96–100PubMedCrossRefGoogle Scholar

Copyright information

© SBIC 2012

Authors and Affiliations

  • Allison S. Harney
    • 1
    • 2
    • 3
    • 4
  • Laura B. Sole
    • 1
    • 2
    • 3
    • 4
  • Thomas J. Meade
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of ChemistryNorthwestern UniversityEvanstonUSA
  2. 2.Department of Molecular BiosciencesNorthwestern UniversityEvanstonUSA
  3. 3.Department of Neurobiology and PhysiologyNorthwestern UniversityEvanstonUSA
  4. 4.Department of RadiologyNorthwestern UniversityEvanstonUSA

Personalised recommendations