Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes.
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.
Ramazzina
Ileana
I
Dipartimento di Biochimica e Biologia molecolare, Università di Parma, 43100 Parma, Italy.
Folli
Claudia
C
Secchi
Andrea
A
Berni
Rodolfo
R
Percudani
Riccardo
R
D000481:Allantoin / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000581:Amidohydrolases / Q000737:chemistry / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002262:Carboxy-Lyases / Q000737:chemistry / Q000235:genetics; D002384:Catalysis; D017124:Conserved Sequence; D016678:Genome; D048288:Imidazolines / Q000737:chemistry; D051379:Mice; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010802:Phylogeny; D013237:Stereoisomerism; D014503:Urate Oxidase / Q000737:chemistry; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry; D014527:Uric Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*
C510198:2-oxo-4-hydroxy-4-carboxy--5-ureidoimidazoline; C510200:5-hydroxyisourate; D048288:Imidazolines; D014527:Uric Acid; D000481:Allantoin; D014508:Urea; D014503:Urate Oxidase; D000581:Amidohydrolases; C474249:hydroxyisourate hydrolase; C510199:2-oxo-4-hydroxy-4-carboxy--5-ureidoimidazoline decarboxylase, mouse; D002262:Carboxy-Lyases