The catalytic activity of xanthine oxidase: mechanistic insights through computer modelling

Abstract

The catalytic cycle for substrate oxidation at the molybdenum centre of xanthine oxidase has been modelled with density functional theory; using our previously developed active-site model plus formaldehyde as substrate, the structures and relative energies of intermediate and transition-state species have been employed to examine the key issues of active-site conformation, the role of Mo–C interactions and the identity of the transferred oxygen.

References

1. R. Hille, JBIC, 1996, 1, 397; Chem. Rev., 1996, 96, 2757.
2. M. R. Bray and R. J. Deeth, Inorg. Chem., 1996, 35, 5270.
3. (a) R. Hille, G. N. George, M. K. Eidness and S. P. Cramer, Inorg. Chem., 1989, 28, 4018; (b) N. A. Turner, R. C. Bray and G. P. Diakun, Biochem. J., 1989, 260, 563 and refs. therein.
4. R. C. Bray, Adv. Enzymol. Relat. Areas Mol. Biol., 1980, 51, 107; R. C. Bray and S. Gutteridge, Biochemistry, 1982, 21, 5992; R. C. Bray and G. N. George, Biochem. Soc. Trans., 1985, 13, 560; G. N. George and R. C. Bray, Biochemistry, 1988, 27, 3603.
5. B. D. Howes, R. C. Bray, R. L. Richards, N. A. Turner, B. Bennett and D. J. Lowe, Biochemistry, 1996, 35, 1432.
6. R. J. Greenwood, G. L. Wilson, J. R. Pilbrow and A. G. Wedd, J. Am. Chem. Soc., 1993, 115, 5385.
7. M. J. Romao, M. Archer, I. Moura, J. J. G. Moura, J. LeGall, R. Engh, M. Schneider, P. Hof and R. Huber, Science, 1995, 270, 1170.
8. R. Huber, P. Hof, R. O. Duarte, J. J. G. Moura, I. Moura, M. Y. Liu, J. LeGall, R. Hille, M. Archer and M. J. Romao, Proc. Natl. Acad. Sci. USA, 1996, 93, 8846.
9. E. J. Baerends, D. E. Ellis and P. Ros, Chem. Phys., 1973, 2, 41; B. te Velde and E. J. Baerends, Int. J. Quantum Chem., 1988, 33, 87.
10. S. H. Vosko, L. Wilk and M. Nusair, Can. J. Phys., 1980, 58, 1200.
11. ADF version 2.0.1 basis sets IV used as supplied, 1996.
12. E. J. Baerends, D. E. Ellis and P. Ros, Theor. Chim. Acta, 1972, 27, 339.
13. A. Becke, Chem. Phys., 1986, 84, 4524.
14. J. P. Perdew, Phys. Rev. B, 1986, 33, 8822; 1987, 34, 7406.
15. R. J. Deeth and L. I. Elding, Inorg. Chem., 1996, 35, 5019.
16. K. N. Murray, J. G. Watson and S. Chaykin, J. Biol. Chem., 1966, 241, 4798.
17. R. Hille and H. J. Sprecher, J. Biol. Chem., 1987, 262, 10 914.
18. R. Hille, Biochim. Biophys. Acta, 1994, 1184, 143.