Evolutionary history and metabolic insights of ancient mammalian uricases

Abstract

Uricase is an enzyme involved in purine catabolism and is found in all three domains of life. Curiously, uricase is not functional in some organisms despite its role in converting highly insoluble uric acid into 5-hydroxyisourate. Of particular interest is the observation that apes, including humans, cannot oxidize uric acid, and it appears that multiple, independent evolutionary events led to the silencing or pseudogenization of the uricase gene in ancestral apes. Various arguments have been made to suggest why natural selection would allow the accumulation of uric acid despite the physiological consequences of crystallized monosodium urate acutely causing liver/kidney damage or chronically causing gout. We have applied evolutionary models to understand the history of primate uricases by resurrecting ancestral mammalian intermediates before the pseudogenization events of this gene family. Resurrected proteins reveal that ancestral uricases have steadily decreased in activity since the last common ancestor of mammals gave rise to descendent primate lineages. We were also able to determine the 3D distribution of amino acid replacements as they accumulated during evolutionary history by crystallizing a mammalian uricase protein.Further, ancient and modern uricases were stably transfected into HepG2 liver cells to test one hypothesis that uricase pseudogenization allowed ancient frugivorous apes to rapidly convert fructose into fat. Finally, pharmacokinetics of an ancient uricase injected in rodents suggest that our integrated approach provides the foundation for an evolutionarily-engineered enzyme capable of treating gout and preventing tumor lysis syndrome in human patients.hyperuricemia | pseudogene | evolution

Ancient insights into uric acid metabolism in primates

“…Although intuitively appealing, conclusive genetic evidence for positive selection on genes that increase the risk of diabetes in human evolution, a key prediction based on Neel's hypothesis, has been surprisingly difficult to demonstrate (3). The results of Kratzer et al (13) do provide convincing experimental evidence for notable declines in uricase activity that could be consistent with ancient physiological adaptations for more efficient processing of fructose and to increase fat stores in times of scarcity (21). It is also evident that loss of uricase activity is an important factor in the high rates of gout and hypertension prevalent today and may be a risk factor for diabetes and obesity as well (14).…”

“…Regardless of why pseudogenes originate, few studies have directly addressed the evolutionary history of their functional decline; in the absence of evidence, it might be tempting to simply assume an abrupt loss of function. However, the authors demonstrate that for primate uricases, this is clearly not the case (13). Their results indicate marked but gradual decreases in uricase function tens of millions of years before pseudogenization likely occurred, with specific activity all but abolished by the time the gene is lost.…”

“…This is the approach taken by Kratzer et al (13) in PNAS to address the fascinating question of why certain primates have lost uricase, a key enzyme that metabolizes uric acid, leaving us vulnerable to diseases such as gout that are not prevalent in other mammals. Uricases are liver enzymes involved in purine metabolism that convert uric acid into a more water-soluble form that is easily excreted by the kidneys (14).…”

“…Disrupting uricase function in mice results in mortality within the first 4 wk of life due to extreme uric acid levels in the blood (16). Kratzer et al (13) used experimentally recreated ancient uricases to determine exactly when, and how, uricase function was lost in primates. They show notable, but surprisingly gradual, decreases in catalytic efficiency in these resurrected ancient enzymes, until activity was completely abolished in the ancestor of the great apes (Fig.…”

Evolution of the Human Brain: the key roles of DHA (omega-3 fatty acid) and Δ6-desaturase gene

“…Another mutation is located at the splice acceptor site in intron 2 for the chimpanzee and human sequences. An additional nonsense mutation is common for the chimpanzee and human sequences at codon 187 (16 million years ago) (Wu et al, 1992;Kratzer et al, 2014).…”