Urate oxidase: primary structure and evolutionary implications.
Urate oxidase, or uricase (EC 1.7.3.3), is a peroxisomal enzyme that catalyzes the oxidation of uric acid to allantoin in most mammals. In humans and certain other primates, however, the enzyme has been lost by some unknown mechanism. To identify the molecular basis for this loss, urate oxidase cDNA clones were isolated from pig, mouse, and baboon, and their DNA sequences were determined. The mouse urate oxidase open reading frame encodes a 303-amino acid polypeptide, while the pig and baboon urate oxidase cDNAs encode a 304-amino acid polypeptide due to a single codon deletion/insertion event. The authenticity of this single additional codon was confirmed by sequencing the mouse and pig genomic copies of the gene. The urate oxidase sequence contains a domain similar to the type 2 copper binding motif found in other copper binding proteins, suggesting that the copper ion in urate oxidase is coordinated as a type 2 structure. Based upon a comparison of the NH2-terminal peptide and deduced sequences, we propose that the maturation of pig urate oxidase involves the posttranslational cleavage of a six-amino acid peptide. Two nonsense mutations were found in the human urate oxidase gene, which confirms, at the molecular level, that the urate oxidase gene in humans is nonfunctional. The sequence comparisons favor the hypothesis that the loss of urate oxidase in humans is due to a sudden mutational event rather than a progressive mutational process.
Wu
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Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030.
Lee
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Muzny
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Caskey
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D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D005784:Gene Amplification; D005796:Genes; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010215:Papio; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity; D013552:Swine; D014503:Urate Oxidase / Q000235:genetics*
D004247:DNA; D014503:Urate Oxidase