Urate oxidase: primary structure and evolutionary implications.

Abstract

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.

Nitrogen recycling and nutritional provisioning byBlattabacterium, the cockroach endosymbiont

“…Because a cultivation-dependent approach is nearly impossible, we used bioinformatics to explore the Blattabacterium genome for uricolytic capabilities. Uricase catalyzes the first step in aerobic uric acid catabolism to allantoin (44,45), but no genes encoding a uricase were identified. A search of sequence databases for Bacteroidetes genes encoding uricases resulted in nine hits to genes encoding proteins annotated as uricase or as either hydroxyisourate hydrolase or transthyretin-like periplasmic protein.…”

Modulation of serum uric acid levels by inosine in patients with multiple sclerosis does not affect blood pressure

“…1,2 Together with further evolutionary changes, the result is that hominoids have serum UA levels that are regulated by a renal excretion/ reuptake system (reviewed in Rafey et al 3 ), and are at least 10-fold higher than in lower mammals. As homozygous mutation of the uricase gene is lethal in lower mammals, 2 it is reasonable to assume the presence of strong evolutionary pressures for the selection of the primary mutations and the retention of UA in higher primates.…”

Uricase production by a recombinant Hansenula polymorpha strain harboring Candida utilis uricase gene

“…Uricase has been found in mammalian (Wu et al 1989), plant (Suzuki and Verma 1991), and microbial cells (Yazdi et al 2006;Lotfy 2008). Microorganisms, such as bacteria, yeast, and filamentous fungi, are important sources of uricase.…”