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Aspects of the mechanism of catalysis of glucose oxidase: A docking, molecular mechanics and quantum chemical study

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Abstract

The complex structure of glucose oxidase (GOX) with the substrate glucose was determined using a docking algorithm and subsequent molecular dynamics simulations. Semiempirical quantum chemical calculations were used to investigate the role of the enzyme and FAD co-enzyme in the catalytic oxidation of glucose. On the basis of a small active site model, substrate binding residues were determined and heats of formation were computed for the enzyme substrate complex and different potential products of the reductive half reaction. The influence of the protein environment on the active site model was estimated with a point charge model using a mixed QM/MM method. Solvent effects were estimated with a continuum model. Possible modes of action are presented in relation to experimental data and discussed with respect to related enzymes. The calculations indicate that the redox reaction of GOX differs from the corresponding reaction of free flavins as a consequence of the protein environment. One of the active site histidines is involved in substrate binding and stabilization of potential intermediates, whereas the second histidine is a proton acceptor. The former one, being conserved in a series of oxidoreductases, is also involved in the stabilization of a C4a-hydroperoxy dihydroflavin in the course of the oxidative half reaction.

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References

  1. Combs, B.S., Carper, W.R. and Stewart, J.J.P., J. Mol. Struct. (THEOCHEM), 258 (1992) 235.

    Google Scholar 

  2. Weibel, M.K. and Bright, H.J., J. Biol. Chem., 246 (1971) 2734.

    Google Scholar 

  3. Müller, F., In Müller, F. (Ed.) Chemistry and Biochemistry of Flavoenzymes, Vol. 1, CRC Press, Boca Raton, FL, 1991, pp. 1–71.

    Google Scholar 

  4. Cavener, D.R., J. Mol. Biol., 223 (1992) 811.

    Google Scholar 

  5. Ritter von Onciul, A. and Clark, T., J. Comput. Chem., 14 (1993) 392.

    Google Scholar 

  6. Ciarkowski, J. and Oldziej, S., Eur. Biophys. J., 22 (1993) 207.

    Google Scholar 

  7. Andrés, J., Safort, V.S., Martins, J.B.L., Beltrán, A. and Moliner, V., J. Mol. Struct. (THEOCHEM), 330 (1995) 411.

    Google Scholar 

  8. Venanzi, T.J., Bryant, B.P. and Venanzi, C.A., J. Comput.-Aided Mol. Design, 9 (1995) 439.

    Google Scholar 

  9. Chang, C.-C. and Huang, P.C., Protein Eng.,9 (1996) 1165.

    Google Scholar 

  10. Silva, A.M., Cachau, R.E., Sham, H.L. and Erickson, J.W., J. Mol. Biol., 255 (1996) 321.

    Google Scholar 

  11. Stavrev, K.K. and Zerner, M.C., Chem. Eur. J., 2 (1996) 83.

    Google Scholar 

  12. Cunningham, M.A., Ho, L.L., Nguyen, D.T., Gillian, R.E. and Bash, A., Biochemistry, 36 (1997) 4800.

    Google Scholar 

  13. Peräkylä, M. and Pakkanen, T.A., J. Am. Chem. Soc., 115 (1993) 10958.

    Google Scholar 

  14. Beveridge, A.J. and Ollis, D.L., Protein Eng., 8 (1995) 135.

    Google Scholar 

  15. Damborský, J., Kutý, M., Němec, M. and Koča, J., J. Chem. Inf. Comput. Sci., 37 (1997) 562.

    Google Scholar 

  16. Hu, H., Liu, H. and Shi, Y., Proteins, 27 (1997) 545.

    Google Scholar 

  17. Mulholland, A.J. and Richards, W.G., Proteins, 27 (1997) 9.

    Google Scholar 

  18. Wladkowski, B.D., Krauss, M. and Stevens, W.J., J. Am. Chem. Soc., 117 (1995) 10357.

    Google Scholar 

  19. Alagona, G., Ghio, C. and Kollman, P.A., J. Mol. Struct. (THEOCHEM), 371 (1996) 287.

    Google Scholar 

  20. Lee, H., Darden, T.A. and Pedersen, L.G., J. Am. Chem. Soc., 118 (1996) 3946.

    Google Scholar 

  21. Garmer, D.R., J. Phys. Chem., B101 (1997) 2945.

    Google Scholar 

  22. Mulholland, A.J., Grant, G.H. and Richards, W.G., Protein Eng., 6 (1993) 133.

    Google Scholar 

  23. Hecht, H.J., Kalisz, H.M., Hendle, J., Schmid, R.D. and Schomburg, D., J. Mol. Biol., 229 (1993) 153.

    Google Scholar 

  24. Meyer, M., Wilson, P. and Schomburg, D., J. Mol. Biol., 264 (1996) 199.

    Google Scholar 

  25. Chu, S.S.C. and Jeffrey, G.A, Acta Crystallogr., 24 (1968) 830.

    Google Scholar 

  26. Schomburg, D. and Reichelt, J., J. Mol. Graph., 6 (1988) 161.

    Google Scholar 

  27. Pearlman, D.A., Case, D.A., Caldwell, J.C., Seibel, G.L., Singh, U.C., Weiner, P. and Kollman, P.A, AMBER 4.0, University of California, San Francisco, CA, U.S.A., 1991.

    Google Scholar 

  28. Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R., Merz, K.M., Ferguson, D.M., Spellmeyer, D.C., Fox, T., Caldwell, J.W. and Kollman, P.A., J. Am. Chem. Soc., 117 (1995) 5179.

    Google Scholar 

  29. Woods, R.J., Dwek, R.A. and Fraser-Reid, B., J. Phys. Chem., 99 (1995) 3832.

    Google Scholar 

  30. Voet, J.G., Coe, J., Epstein, J., Matossian, V. and Shipley, T., Biochemistry, 20 (1981) 7182.

    Google Scholar 

  31. Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Imey, R. and Klein, M., J. Chem. Phys., 79 (1983) 926.

    Google Scholar 

  32. Ryckaert, J.P., Cicotti, G. and Berendsen, H.J.C., J. Comput. Phys., 23 (1977) 327.

    Google Scholar 

  33. Cox, S.R. and Williams, D.E., J. Comput. Chem., 2 (1981) 304.

    Google Scholar 

  34. Singh, U.C. and Kollman, P.A., J. Comput. Chem., 5 (1984) 129.

    Google Scholar 

  35. Lee, C., Yang, W. and Parr, R.G., Phys. Rev., B37 (1988) 785.

    Google Scholar 

  36. Becke, A.D., J. Chem. Phys., 98 (1993) 5648.

    Google Scholar 

  37. Hehre, W.J., Ditchfield, R. and Pople, J.A., J. Chem. Phys., 56 (1972) 2257.

    Google Scholar 

  38. Peräkyla, M. and Pakkanen, T.A., Proteins, 21 (1995) 22.

    Google Scholar 

  39. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Gill, P.M.W., Johnson, B.G., Robb, M.A., Cheeseman, J.R., Keith, T., Petersson, G.A., Montgomery, J.A., Raghavachari, K., Al-Laham, M.A., Zakrzewski, V.G., Ortiz, J.V., Foresman, J.B., Cioslowski, J., Stefanov, B.B., Nanayakkara, A., Challacombe, M., Peng, C.Y., Ayala, P.Y., Chen, W., Wong, M.W., Andres, J.L., Replogle, E.S., Gomperts, R., Martin, R.L., Fox, D.J., Binkley, J.S., Defrees, D.J., Baker, J., Stewart, J.P., Head-Gordon, M., Gonzalez, C. and Pople J.A., GAUSSIAN 94, Revision B.3, Gaussian Inc., Pittsburgh, PA, U.S.A., 1995.

    Google Scholar 

  40. Schmidt, M.W., Baldridge, K.K., Boatz, J.A., Elbert, T.S., Gordon, M.S., Jensen, J.H., Koseki, S., Matsunaga, N., Nguyen, K.A., Su, S., Windus, T.L., Dupuis, M. and Montgomery, J., J. Comput. Chem., 14 (1993) 1347.

    Google Scholar 

  41. Stewart, J.J.P., J. Comput. Chem., 10 (1989) 209.

    Google Scholar 

  42. Vamp 6.1, Oxford Molecular Ltd., Magdalen Centre, Oxford Science Park, Sandford-on-Thames, Oxford OX4 4GA, U.K.

  43. Hawkins, G.D., Lynch, G.C., Giessen, D.J., Rossi, I., Storer, J.W., Liotard, D.A., Cramer, C.J. and Truhlar, D.G., AMSOL 5.4 Quantum Chemistry Exchange Program 606, based in part on AMPAC 2.1, Liotard, D.A., Healy, E.F., Ruiz, J.M. and Dewar, M.J.S.

  44. Liotard, D.A., Hawkins, G.D., Lynch, G.C., Truhlar, D.G. and Cramer, C.J., J. Comput. Chem., 16 (1995) 422.

    Google Scholar 

  45. Beck, B., Rauhut, G. and Clark, T., J. Comput. Chem., 15 (1994) 1064.

    Google Scholar 

  46. Kohen, A., Jonsson, T. and Klinman, J.P., Biochemistry, 36 (1997) 2603.

    Google Scholar 

  47. Stewart, J.J.P., J. Comput.-Aided Mol. Design, 4 (1990) 1.

    Google Scholar 

  48. Meyer, M., J. Mol. Struct. (THEOCHEM), 304 (1994) 45.

    Google Scholar 

  49. NIST Chemistry Web Book, NIST Standard Reference Database Number 69, August1997 Release (http://webbook.nist.gov/chemistry). Proton affinity data compiled and evaluated by E.D. Hunter and S.G. Lias.

  50. Schröder, S., Daggett, V. and Kollman, P.A., J. Am. Chem. Soc., 113 (1991) 8922.

    Google Scholar 

  51. Meyer, M., Hartwig, H. and Schomburg, D., J. Mol. Struct. (THEOCHEM), 364 (1996) 139.

    Google Scholar 

  52. Zheng, Y.-J. and Ornstein, R.L., J. Am. Chem. Soc., 118 (1996) 9402.

    Google Scholar 

  53. Meyer, M., J. Mol. Struct. (THEOCHEM), 417 (1997) 163.

    Google Scholar 

  54. Wouters, J., Durant, F., Champagne, B. and André, J.-M., Int. J. Quantum Chem., 64 (1997) 721.

    Google Scholar 

  55. Massey, V., J. Biol. Chem., 269 (1994) 22459.

    Google Scholar 

  56. Jurema, M.W. and Shields, G.C., J. Comput. Chem., 14 (1992) 89.

    Google Scholar 

  57. Lively, T.N., Jurema, M.W. and Shields, G.C., Int. J. Quantum Chem., 21 (1994) 95.

    Google Scholar 

  58. Kallies, B. and Mitzner, R., J. Mol. Model., 1 (1995) 68.

    Google Scholar 

  59. Manstein, D.J., Pai, F., Schopfer, L.M. and Massey, V., Biochemistry, 25 (1986) 6807.

    Google Scholar 

  60. Sanner, C., Macheroux, P., Rüterjans, H., Müller, F. and Bacher, A., Eur. J. Biochem., 196 (1991) 663.

    Google Scholar 

  61. Li, J., Vrielink, A., Brick, P. and Blow, D.M., Biochemistry, 32 (1993) 11507.

    Google Scholar 

  62. Derewenda, Z.S., Derewenda, U. and Kobos, P.M., J. Mol. Biol., 241 (1994) 83.

    Google Scholar 

  63. Wahl, M.C. and Sundaralingam, M., Trends Biochem. Sci., 22 (1997) 97.

    Google Scholar 

  64. Ornstein, R.L. and Zheng, Y.L., J. Biomol. Struct. Dyn., 14 (1997) 657.

    Google Scholar 

  65. Kraulis, P., J. Appl. Crystallogr., 24 (1991) 946.

    Google Scholar 

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Authors and Affiliations

  1. Institut für Molekulare Biotechnologie (IMB), Biocomputing, Beutenbergstrasse 11, D-07745, Jena, Germany

    Michael Meyer

  2. Gesellschaft für Biotechnologische Forschung (GBF), Abt. Enzymologie, Germany

    Gerd Wohlfahrt

  3. Molekulare Strukturforschung, Mascheroder Weg 1, D-38124, Braunschweig, Germany

    Jörg Knäblein & Dietmar Schomburg

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  1. Michael Meyer
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  4. Dietmar Schomburg
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Meyer, M., Wohlfahrt, G., Knäblein, J. et al. Aspects of the mechanism of catalysis of glucose oxidase: A docking, molecular mechanics and quantum chemical study. J Comput Aided Mol Des 12, 425–440 (1998). https://doi.org/10.1023/A:1008020124326

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