Loss of Urate Oxidase Activity in Hominoids and its Evolutionary Implications

Abstract

We have determined and compared the promoter, coding, and intronic sequences of the urate oxidase (Uox) gene of various primate species. Although we confirm the previous observation that the inactivation of the gene in the clade of the human and the great apes results from a single CGA to TGA nonsense mutation in exon 2, we find that the inactivation in the gibbon lineage results from an independent nonsense mutation at a different CGA codon in exon 2 or from either one-base deletion in exon 3 or one-base insertion in exon 5, contrary to the previous claim that the cause is a 13-bp deletion in exon 2. We also find that compared with other organisms, the primate functional Uox gene is exceptional in terms of usage of CGA codons which are prone to TGA nonsense mutations. Nevertheless, we demonstrate rather strong selective constraint against nonsynonymous sites of the functional Uox gene and argue that this observation is consistent with the fact that the Uox gene is unique in the genome and evolutionarily conserved not only among animals but also among eukaryotes. Another finding that there are a few substitutions in the cis-acting element or CAAT-box (or both) of primate functional Uox genes may explain the lowered transcriptional activity. We suggest that although the inactivation of the hominoid Uox gene was caused by independent nonsense or frameshift mutations, the gene has taken a two-step deterioration process, first in the promoter and second in the coding region during primate evolution. It is also argued that the high concentration of uric acid in the blood of humans and nonhuman primates has developed molecular coevolution with the xanthine oxidoreductase in purine metabolism. However, it remains to be answered whether loss of Uox activity in hominoids is related to protection from oxidative damage and the prolonged life span.

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

“…Urate is the end product of purine metabolism in humans, who have lost the expression of the uricase gene during evolution (3). Urate is freely filtered by the glomerulus and essentially reabsorbed, because only 10% of the filtered load is present in the final urine (4).…”

Uric acid transport and disease

“…Whereas in humans and the great apes, uric acid is the end product of purine degradation, in other mammals, it is further degraded into allantoin by uricase, an enzyme that is mostly found in the liver. The gene encoding uricase underwent mutational silencing during hominid evolution (1). The consequence of uricase inactivation is the appearance of urate levels that are much higher in humans (≈240-360 μM) in comparison to other mammals (≈30-50 μM in mice).…”

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

“…Higher primates (apes and humans) lack functional uricase and excrete uric acid as the end product of purine degradation, which is a causative factor of gout (Oda et al 2002). Allopurinol is generally used to treat gout.…”