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

Nat Chem Biol. 2006 Mar;2(3):144-8. doi: 10.1038/nchembio768. Epub 2006 Feb 5.


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 conversion. However, detailed studies of the mechanism and regiochemistry of urate oxidation 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allantoin / chemical synthesis
  • Allantoin / chemistry
  • Allantoin / metabolism
  • Amidohydrolases / chemistry
  • Amidohydrolases / genetics
  • Amino Acid Sequence
  • Animals
  • Carboxy-Lyases / chemistry
  • Carboxy-Lyases / genetics
  • Catalysis
  • Conserved Sequence
  • Genome*
  • Imidazolines / chemistry
  • Mice
  • Molecular Conformation
  • Molecular Sequence Data
  • Molecular Structure
  • Oxidation-Reduction
  • Phylogeny*
  • Stereoisomerism
  • Urate Oxidase / chemistry
  • Urea / analogs & derivatives
  • Urea / chemistry
  • Uric Acid / analogs & derivatives
  • Uric Acid / chemistry
  • Uric Acid / metabolism*


  • 2-oxo-4-hydroxy-4-carboxy--5-ureidoimidazoline
  • 5-hydroxyisourate
  • Imidazolines
  • Uric Acid
  • Allantoin
  • Urea
  • Urate Oxidase
  • Amidohydrolases
  • hydroxyisourate hydrolase
  • 2-oxo-4-hydroxy-4-carboxy--5-ureidoimidazoline decarboxylase, mouse
  • Carboxy-Lyases

Associated data

  • GENBANK/DQ225767
  • GENBANK/DQ225768
  • PubChem-Substance/8036878
  • PubChem-Substance/8036879
  • PubChem-Substance/8036880
  • PubChem-Substance/8036881