Cobalamins are the largest and structurally complex cofactors found in biological systems and have attracted considerable attention due to their participation in the metabolic reactions taking place in humans, animals, and microorganisms. Riboflavin (vitamin B2) is a micronutrient and is the precursor of coenzymes, FMN and FAD, required for a wide variety of cellular processes with a key role in energy-based metabolic reactions. As coenzymes of both vitamins are the part of enzyme systems, the possibility of their mutual interaction in the body cannot be overruled. A molecular docking study was conducted on riboflavin molecule with B12 coenzymes present in the enzymes glutamate mutase, diol dehydratase, and methionine synthase by using ArgusLab 4.0.1 software to understand the possible mode of interaction between these vitamins. The results from ArgusLab showed the best binding affinity of riboflavin with the enzyme glutamate mutase for which the calculated least binding energy has been found to be ？7.13？kcal/mol. The results indicate a significant inhibitory effect of riboflavin on the catalysis of B12-dependent enzymes. This information can be utilized to design potent therapeutic drugs having structural similarity to that of riboflavin. 1. Introduction B12 cofactors play important roles in the metabolism of microorganisms, animals, and humans. They are involved in the metabolism of almost every cell of the body specifically the DNA synthesis and regulation. The structure and reactivity of B12 derivatives and structural aspects of their interactions with proteins and nucleotides are crucial for the efficient catalysis by the important B12-dependent enzymes [1]. Biologically active cobalamins, adenosylcobalamin (AdoCbl), and methylcobalamin (MeCbl) are cofactors for many enzyme systems, containing a metal carbon bond involved in enzyme catalyzed reactions [2]. They catalyze enzymatic reactions which involve the making and breaking of the C–Co bond of these cofactors. The X-ray structures of B12-enzyme complexes revealed that the B12-cofactor undergoes a major conformational change on binding to the apoenzyme in AdoCbl and MeCbl containing enzymes such as isomerases, eliminases, and methyltransferases [3]. A key step in the catalytic mechanism of coenzyme-B12 containing enzymes is the homolysis of Co–C organometallic bond that leads to the intricate pathways of B12 metabolic functions and the catalysis of related chemical reactions [4]. The Co–C bond undergoes homolytic cleavage in B12-dependent enzymes more quickly as compared to that of the isolated
References
[1]
K. Gruber, B. Puffer, and B. Krautler, “Vitamin B12-derivatives-enzyme cofactors and ligands of proteins and nucleic acids,” Chemical Society Reviews, vol. 40, no. 8, pp. 4346–4363, 2011.
[2]
L. Randaccio, S. Geremia, N. Demitri, and J. Wuerges, “Vitamin B12: unique metalorganic compounds and the most complex vitamins,” Molecules, vol. 15, no. 5, pp. 3228–3259, 2010.
[3]
R. Banerjee and S. W. Ragsdale, “The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes,” Annual Review of Biochemistry, vol. 72, pp. 209–247, 2003.
[4]
R. G. Matthews, “Cobalamin and corrinoid dependent enzymes,” in Metal Ions in Life Sciences, A. Sigel, H. Sigel, and R. K. O. Sigel, Eds., vol. 6, pp. 53–114, Royal Society of Chemistry, Cambridge, UK, 2009.
[5]
P. J. Kasper and U. Ryde, “How the Co-C bond is cleaved in coenzyme B12 enzymes: a theoretical study,” Journal of the American Chemical Society, vol. 127, no. 25, pp. 9117–9128, 2005.
[6]
L. Randaccio, S. Geremia, and J. Wuerges, “Crystallography of vitamin B12 proteins,” Journal of Organometallic Chemistry, vol. 692, no. 6, pp. 1198–1215, 2007.
[7]
B. Kr？utler, “Organometallic chemistry of B12 coenzymes,” in Metal Ions in Life Sciences, A. Sigel, H. Sigel, and R. K. O. Sigel, Eds., vol. 6, pp. 1–51, Royal Society of Chemistry, Cambridge, UK, 2009.
[8]
A. Kahraman, R. J. Morris, R. A. Laskowski, and J. M. Thornton, “Shape variation in protein binding pockets and their ligands,” Journal of Molecular Biology, vol. 368, no. 1, pp. 283–301, 2007.
[9]
S. F. Sousa, P. A. Fernandes, and M. J. Ramos, “Protein-ligand docking: current status and future challenges,” Proteins: Structure, Function and Genetics, vol. 65, no. 1, pp. 15–26, 2006.
[10]
R. D. Taylor, P. J. Jewsbury, and J. W. Essex, “A review of protein-small molecule docking methods,” Journal of Computer-Aided Molecular Design, vol. 16, no. 3, pp. 151–166, 2002.
[11]
M. A. Thompson, “Molecular docking using ArgusLab, an efficient shape-based search algorithm and AScore scoring function,” in Proceedings of the ACS Meeting, Philadelphia, Pa, USA, March-April 2004, 172, CINF 42.
[12]
R. Wang, X. Fang, Y. Lu, and S. Wang, “The PDBbind database: collection of binding affinities for protein-ligand complexes with known three-dimensional structures,” Journal of Medicinal Chemistry, vol. 47, no. 12, pp. 2977–2980, 2004.
[13]
R. Reitzer, K. Gruber, G. Jogl et al., “Glutamate mutase from Clostridium cochlearium: the structure of a coenzyme B12-dependent enzyme provides new mechanistic insights,” Structure, vol. 7, no. 8, pp. 891–902, 1999.
[14]
N. Shibata, J. Masuda, T. Tobimatsu et al., “A new mode of B12 binding and the direct participation of a potassium ion in enzyme catalysis: X-ray structure of diol dehydratase,” Structure, vol. 7, no. 8, pp. 997–1008, 1999.
[15]
M. Koutmos, S. Datta, K. A. Pattridge, J. L. Smith, and R. G. Matthews, “Insights into the reactivation of cobalamin-dependent methionine synthase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 44, pp. 18527–18532, 2009.
[16]
S. Joy, P. S. Nair, R. Hariharan, and M. R. Pillai, “Detailed comparison of the protein-ligand docking efficiencies of GOLD, a commercial package and arguslab, a licensable freeware,” In Silico Biology, vol. 6, no. 6, pp. 601–605, 2006.
[17]
M. Thompson, ArgusLab 4.0.1., Planaria software LLC, Seattle, Wash, USA, 2004.
