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Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes

Nature Chemical Biology volume 2, pages 144–148 (2006)Cite this article

Abstract

Mammals that degrade uric acid are not affected by gout or urate kidney stones. It is not fully understood how they convert uric acid into the much more soluble allantoin. Until recently, it had long been thought that urate oxidase was the only enzyme responsible for this conversion1,2. However, detailed studies of the mechanism and regiochemistry of urate oxidation3,4,5 have called this assumption into question, suggesting the existence of other distinct enzymatic activities. Through phylogenetic genome comparison, we identify here two genes that share with urate oxidase a common history of loss or gain events. We show that the two proteins encoded by mouse genes catalyze two consecutive steps following urate oxidation to 5-hydroxyisourate (HIU): hydrolysis of HIU to give 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) and decarboxylation of OHCU to give S-(+)-allantoin. Urate oxidation produces racemic allantoin on a time scale of hours, whereas the full enzymatic complement produces dextrorotatory allantoin on a time scale of seconds. The use of these enzymes in association with urate oxidase could improve the therapy of hyperuricemia.

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Figure 1: Inferring functional links to urate oxidase through phylogenetic genome comparison.
Figure 2: Roles of HIU hydrolase and OHCU decarboxylase in uric acid degradation.
Figure 3: Sequence comparison of HIU hydrolase and OHCU decarboxylase.

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References

  1. Vogels, G.D. & Van der Drift, C. Degradation of purines and pyrimidines by microorganisms. Bacteriol. Rev. 40, 403–468 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Stryer, L. Biochemistry (W.H. Freeman, New York, 1995).

    Google Scholar 

  3. Modric, N., Derome, A.E., Ashcroft, S.J.H. & Poje, M. Tracing and identification of uricase reaction intermediates. A direct 13C-NMR/isotope-labelling evidence. Tetrahedr. Lett. 33, 6691–6694 (1992).

    Article  CAS  Google Scholar 

  4. Kahn, K., Serfozo, P. & Tipton, P.A. Identification of the true product of the urate oxidase reaction. J. Am. Chem. Soc. 274, 5435–5442 (1997).

    Article  Google Scholar 

  5. Kahn, K. & Tipton, P.A. Spectroscopic characterization of intermediates in the urate oxidase reaction. Biochemistry 37, 11651–11659 (1998).

    Article  CAS  Google Scholar 

  6. Oda, M., Satta, Y., Takenaka, O. & Takahata, N. Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol. Biol. Evol. 19, 640–653 (2002).

    Article  CAS  Google Scholar 

  7. Sarma, A.D., Serfozo, P., Kahn, K. & Tipton, P.A. Identification and purification of hydroxyisourate hydrolase, a novel ureide-metabolizing enzyme. J. Biol. Chem. 274, 33863–33865 (1999).

    Article  CAS  Google Scholar 

  8. Mulrooney, S.B. & Hausinger, R.P. Metal ion dependence of recombinant Escherichia coli allantoinase. J. Bacteriol. 185, 126–134 (2003).

    Article  CAS  Google Scholar 

  9. Snel, B., Bork, P. & Huynen, M.A. The identification of functional modules from the genomic association of genes. Proc. Natl. Acad. Sci. USA 99, 5890–5895 (2002).

    Article  CAS  Google Scholar 

  10. Hurst, L.D., Pal, C. & Lercher, M.J. The evolutionary dynamics of eukaryotic gene order. Nat. Rev. Genet. 5, 299–310 (2004).

    Article  CAS  Google Scholar 

  11. Marcotte, E.M. et al. Detecting protein function and protein-protein interactions from genome sequences. Science 285, 751–753 (1999).

    Article  CAS  Google Scholar 

  12. Pellegrini, M., Marcotte, E.M., Thompson, M.J., Eisenberg, D. & Yeates, T.O. Assigning protein functions by comparative genome analysis: protein phylogenetic profiles. Proc. Natl. Acad. Sci. USA 96, 4285–4288 (1999).

    Article  CAS  Google Scholar 

  13. von Mering, C. et al. STRING: known and predicted protein-protein associations, integrated and transferred across organisms. Nucleic Acids Res. 33, D433–D437 (2005).

    Article  CAS  Google Scholar 

  14. Tatusov, R.L., Koonin, E.V. & Lipman, D.J. A genomic perspective on protein families. Science 278, 631–637 (1997).

    Article  CAS  Google Scholar 

  15. Barker, D. & Pagel, M. Predicting functional gene links from phylogenetic-statistical analyses of whole genomes. PLoS Comput. Biol. 1, e3 (2005).

    Article  Google Scholar 

  16. Schultz, A.C., Nygaard, P. & Saxild, H.H. Functional analysis of 14 genes that constitute the purine catabolic pathway in Bacillus subtilis and evidence for a novel regulon controlled by the PucR transcription activator. J. Bacteriol. 183, 3293–3302 (2001).

    Article  CAS  Google Scholar 

  17. Eneqvist, T., Lundberg, E., Nilsson, L., Abagyan, R. & Sauer-Eriksson, A.E. The transthyretin-related protein family. Eur. J. Biochem. 270, 518–532 (2003).

    Article  CAS  Google Scholar 

  18. Lee, Y. et al. Transthyretin-related proteins function to facilitate the hydrolysis of 5-hydroxyisourate, the end product of the uricase reaction. FEBS Lett. 579, 4769–4774 (2005).

    Article  CAS  Google Scholar 

  19. 's-Gravenmade, E.J., Vogels, G.D. & van Pelt, C. Preparation, properties and absolute configuration of (−)-allantoin. Recl. Trav. Chim. Pays Bas 88, 929–939 (1969).

    Article  CAS  Google Scholar 

  20. Santos, C.X., Anjos, E.I. & Augusto, O. Uric acid oxidation by peroxynitrite: multiple reactions, free radical formation, and amplification of lipid oxidation. Arch. Biochem. Biophys. 372, 285–294 (1999).

    Article  CAS  Google Scholar 

  21. Pitts, O.M. & Priest, D.G. Uricase reaction intermediate. Mechanism of borate and hydroxide ion catalysis. Biochemistry 12, 1358–1363 (1973).

    Article  CAS  Google Scholar 

  22. Bongaerts, G.P. & Vogels, G.D. Mechanism of uricase action. Biochim. Biophys. Acta 567, 295–308 (1979).

    Article  CAS  Google Scholar 

  23. Swinkels, B.W., Gould, S.J., Bodnar, A.G., Rachubinski, R.A. & Subramani, S. A novel, cleavable peroxisomal targeting signal at the amino-terminus of the rat 3-ketoacyl-CoA thiolase. EMBO J. 10, 3255–3262 (1991).

    Article  CAS  Google Scholar 

  24. Hayashi, S., Fujiwara, S. & Noguchi, T. Evolution of urate-degrading enzymes in animal peroxisomes. Cell Biochem. Biophys. 32, 123–129 (2000).

    Article  CAS  Google Scholar 

  25. Gould, S.G., Keller, G.A. & Subramani, S. Identification of a peroxisomal targeting signal at the carboxy terminus of firefly luciferase. J. Cell Biol. 105, 2923–2931 (1987).

    Article  CAS  Google Scholar 

  26. Hall, A.P., Barry, P.E., Dawber, T.R. & McNamara, P.M. Epidemiology of gout and hyperuricemia. A long-term population study. Am. J. Med. 42, 27–37 (1967).

    Article  CAS  Google Scholar 

  27. Bomalaski, J.S. & Clark, M.A. Serum uric acid-lowering therapies: where are we heading in management of hyperuricemia and the potential role of uricase. Curr. Rheumatol. Rep. 6, 240–247 (2004).

    Article  Google Scholar 

  28. Bowers, P.M. et al. Prolinks: a database of protein functional linkages derived from coevolution. Genome Biol. 5, R35 (2004).

    Article  Google Scholar 

  29. Gouet, P., Courcelle, E., Stuart, D.I. & Metoz, F. ESPript: analysis of multiple sequence alignments in PostScript. Bioinformatics 15, 305–308 (1999).

    Article  CAS  Google Scholar 

  30. Zanotti, G., D'Acunto, M.R., Malpeli, G., Folli, C. & Berni, R. Crystal structure of the transthyretin–retinoic-acid complex. Eur. J. Biochem. 234, 563–569 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Acquotti and L. Ronda for technical help, A. Peracchi, A. Merli and G.L. Rossi for discussions and the Centre “G. Casnati” in Parma for providing instrumentation. This study has been partly supported by COFIN2003 and FilRP05.

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Author notes

  1. Ileana Ramazzina and Claudia Folli: These authors contributed equally to this work.

Authors and Affiliations

  1. Dipartimento di Biochimica e Biologia molecolare, Università di Parma, Parma, 43100, Italy

    Ileana Ramazzina, Claudia Folli, Rodolfo Berni & Riccardo Percudani

  2. Dipartimento di Chimica organica e industriale, Università di Parma, Parma, 43100, Italy

    Andrea Secchi

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  1. Ileana Ramazzina
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Correspondence to Riccardo Percudani.

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Supplementary information

Supplementary Fig. 1

13C NMR of the conversion of [15N, 13C]urate catalysed by UO, HIU hydrolase and OHCU decarboxylase. (PDF 322 kb)

Supplementary Table 1

Predicted functional association of urate oxidase (COG3648). (PDF 11 kb)

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Ramazzina, I., Folli, C., Secchi, A. et al. Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes. Nat Chem Biol 2, 144–148 (2006). https://doi.org/10.1038/nchembio768

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