ABC  Vol.2 No.2 , May 2012
Interaction of CORM-2 with hydrophobic sites: Beyond CO
ABSTRACT
Carbon monoxide releasing molecules (CORMs) have been recently developed for research and pharmacological purposes. A considerable amount of studies demonstrated a wide spectrum of biological activities for lipophilic CORM-2 (tricarbonyldichlororuthenium (II) dimer). It is generally accepted that the liberated gas provides the specific activities to CORMs, with a little attention paid to any possible effect of complementary core molecules. However, the versatile repertoire of actions attributed to CORM-2 is surprisingly wide for CO, a molecule with the sole chemical activity of binding to ferrous iron in protein prosthetic groups. The study was designed to analyze CORM-2 and its core molecule (“i”CORM) activities at a molecular level. With respect to the hydrophobic nature of the compounds, we followed their interactions with several amphipathic entities: the heme sites of hemoproteins, heme binding proteins and cell membranes. CORM-2/“i”CORM decreased the Soret optical density of hemoglobin and myoglobin, indicating that both compounds interact with the protein amphipathic site in the heme pocket. Pre-addition of CORM-2/“i”CORM to the apo-forms of the plasma heme binding proteins, hemopexin and albumin, partially abolished their heme binding capacity. In contrast, the compounds had no effect on the preformed heme-protein complexes. Addition of CORM-2/“i”- CORM to blood or isolated erythrocytes revealed aggregation of the cells or lysis, depending on the rea-gent-to-cells ratio. It was concluded that the ruthenium containing core molecule of CORM-2 may be physiologically active due to non-specific hydrophobic interactions. As each type of CORMs is expected to have a different mode of action beyond CO activity, their potential therapeutic uses will require clarification.

Cite this paper
Sher, E. , Shaklai, M. and Shaklai, N. (2012) Interaction of CORM-2 with hydrophobic sites: Beyond CO. Advances in Biological Chemistry, 2, 191-197. doi: 10.4236/abc.2012.22023.
References
[1]   Ryter, S.W. and Choi, A.M. (2009) Heme oxygenase- 1/carbon monoxide: from metabolism to molecular therapy. American Journal of Respiratory Cell and Molecular Biology, 41, 251-260. doi:10.1165/rcmb.2009-0170TR

[2]   Gozzelino, R., Jeney, V. and Soares, M.P. (2010) Mechanisms of cell protection by heme oxygenase-1. Annual Review of Pharmacology and Toxicology, 50, 323-354. doi:10.1146/annurev.pharmtox.010909.105600

[3]   Motterlini, R., Clark, J.E. and Foresti, R., et al. (2002) Carbon monoxide-releasing molecules: Characterization of biochemical and vascular activities. Circulation Research, 90, 17-24. doi:10.1161/hh0202.104530

[4]   Dong, D.L., Chen, C. and Huang, W., et al. (2008) Tricarbonyldichlororuthenium (II) dimer (CORM2) activates non-selective cation current in human endothelial cells independently of carbon monoxide releasing. European Journal of Pharmacology, 590, 99-104. doi:10.1016/j.ejphar.2008.05.042

[5]   Wilkinson, W.J. and Kemp, P.J. (2011) The carbon monoxide donor, CORM-2, is an antagonist of ATP-gated, human P2X4 receptors. Purinergic Signalling, 7, 57-64. doi:10.1007/s11302-010-9213-8

[6]   Nielsen, V.G., Kirklin, J.K. and George, J.F. (2009) Carbon monoxide-releasing molecule-2 increases the velocity of thrombus growth and strength in human plasma. Blood Coagulation & Fibrinolysis, 20, 377-380. doi:10.1097/MBC.0b013e32832ca3a3

[7]   Deshane, J., Chen, S. and Caballero, S., et al. (2007) Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism. The Journal of Experimental Medicine, 204, 605-618. doi:10.1084/jem.20061609

[8]   Motterlini, R. and Otterbein, L.E. (2010) The therapeutic potential of carbon monoxide. Nature Reviews Drug Discovery, 9, 728-743. doi:10.1038/nrd3228

[9]   Antonini, M.E. and Brunori, M. (1971) The derivatives of ferric hemoglobin and myoglobin. North-Holland Publishing Company, Amsterdam.

[10]   Ueno, R., Shimizu, T. and Kondo, K., et al. (1982) Activation mechanism of prostaglandin endoperoxide synthetase by hemoproteins. The Journal of Biological Chemistry, 257, 5584-5588.

[11]   Hrkal, Z., Cabart, P. and Kalousek, I. (1992) Isolation of human haemopexin in apo-form by chromatography on S-Sepharose Fast Flow and Blue Sepharose CL-6B. Biomedical Chromatography, 6, 212-214. doi:10.1002/bmc.1130060412

[12]   Tsemakhovitch, V.A., Bamm, V.V. and Shaklai, N. (2005) Vascular damage by unstable hemoglobins: the role of heme-depleted globin. Archives of Biochemistry and Bio- physics, 436, 307-315. doi:10.1016/j.abb.2005.02.006

[13]   Hirota, S., Azuma, K. and Fukuba, M., et al. (2005) Heme reduction by intramolecular electron transfer in cysteine mutant myoglobin under carbon monoxide atmosphere. Biochemistry, 44, 10322-10327. doi:10.1021/bi0507581

[14]   Prabhu, N.P., Kumar, R. and Bhuyan, A.K. (2004) Folding barrier in horse cytochrome c: Support for a classical folding pathway. Journal of Molecular Biology, 337, 195- 208. doi: 10.1016/j.jmb.2004.01.016

[15]   Bunn, H.F. and Jandl, J.H. (1968) Exchange of heme among hemoglobins and between hemoglobin and albumin. The Journal of Biological Chemistry, 243, 465-475.

[16]   Liem, H.H., Spector, J.I. and Conway, T.P., et al. (1975) Effect of hemoglobin and hematin on plasma clearance of hemopexin, photo-inactivated hemopexin and albumin. Proceedings of the Society for Experimental Biology, 148, 519-522.

[17]   Paoli, M., Anderson, B.F. and Baker, H.M., et al. (1999) Crystal structure of hemopexin reveals a novel high-affinity heme site formed between two beta-propeller domains. Nature Structural & Molecular Biology, 6, 926- 931. doi:10.1038/13294

[18]   Beaven, G.H., Chen, S.H., d’Albis, A. and Gratzer, W.B. (1974) A spectroscopic study of the haemin-human-se- rum-albumin system. European Journal of Biochemistry, 41, 539-546. doi:10.1111/j.1432-1033.1974.tb03295.x

[19]   Zunszain, P.A., Ghuman, J. and Komatsu T., et al. (2003) Crystal structural analysis of human serum albumin complexed with hemin and fatty acid. BMC Structural Biology, 3, 6. doi:10.1186/1472-6807-3-6

[20]   Yang, Z., Philips, J.D. and Doty, R.T., et al. (2010) Kinetics and specificity of feline leukemia virus subgroup C receptor (FLVCR) export function and its dependence on hemopexin. The Journal of Biological Chemistry, 285, 28874-28882. doi:10.1074/jbc.M110.119131

[21]   Baroni, S., Mattu, M. and Vannini, A., et al. (2001) Effect of ibuprofen and warfarin on the allosteric properties of haem-human serum albumin. A spectroscopic study. European Journal of Biochemistry, 268, 6214-6220. doi:10.1046/j.0014-2956.2001.02569.x

[22]   Valerie, N.G. (2009) Chemical-associated artifacts. Blood, 113, 4487.

[23]   Nielsen, V.G., Cohen, J.B. and Malayaman, S.N., et al. (2011) Fibrinogen is a heme-associated, carbon monoxide sensing molecule: A preliminary report. Blood Coagulation & Fibrinolysis, 22, 443-447. doi: 10.1097/MBC.0b013e328345c069

[24]   van Oss, C.J. (1990) Surface properties of fibrinogen and fibrin. Journal of Protein Chemistry, 9, 487-491. doi: 10.1007/BF01024625

 
 
Top