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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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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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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DOI: https://doi.org/10.1038/nchembio768
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