The structure of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase provides insights into the mechanism of uric acid degradation

J Biol Chem. 2007 Jun 22;282(25):18182-18189. doi: 10.1074/jbc.M701297200. Epub 2007 Apr 11.


The complete degradation of uric acid to (S)-allantoin, as recently elucidated, involves three enzymatic reactions. Inactivation by pseudogenization of the genes of the pathway occurred during hominoid evolution, resulting in a high concentration of urate in the blood and susceptibility to gout. Here, we describe the 1.8A resolution crystal structure of the homodimeric 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase, which catalyzes the last step in the urate degradation pathway, for both ligand-free enzyme and enzyme in complex with the substrate analogs (R)-allantoin and guanine. Each monomer comprises ten alpha-helices, grouped into two domains and assembled in a novel fold. The structure and the mutational analysis of the active site have allowed us to identify some residues that are essential for catalysis, among which His-67 and Glu-87 appear to play a particularly significant role. Glu-87 may facilitate the exit of the carboxylate group because of electrostatic repulsion that destabilizes the ground state of the substrate, whereas His-67 is likely to be involved in a protonation step leading to the stereoselective formation of the (S)-allantoin enantiomer as reaction product. The structural and functional characterization of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase can provide useful information in view of the potential use of this enzyme in the enzymatic therapy of gout.

MeSH terms

  • Allantoin / pharmacology
  • Amino Acid Sequence
  • Animals
  • Carboxy-Lyases / chemistry
  • Carboxy-Lyases / physiology*
  • Crystallography, X-Ray
  • DNA Mutational Analysis
  • Glutamic Acid / chemistry
  • Guanine / pharmacology
  • Histidine / chemistry
  • Ligands
  • Models, Chemical
  • Molecular Sequence Data
  • Protein Folding
  • Uric Acid / metabolism*
  • Zebrafish
  • Zebrafish Proteins / chemistry*
  • Zebrafish Proteins / physiology*


  • Ligands
  • Zebrafish Proteins
  • Uric Acid
  • Allantoin
  • Glutamic Acid
  • Histidine
  • Guanine
  • 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase, zebrafish
  • Carboxy-Lyases

Associated data

  • GENBANK/EF197726
  • PDB/2O70
  • PDB/2O73
  • PDB/2O74