Phylogenetic Articulation of Uric Acid Evolution in Mammals and How It Informs a Therapeutic Uricase

Abstract

The role of uric acid during primate evolution has remained elusive ever since it was discovered over 100 years ago that humans have unusually high levels of the small molecule in our serum. It has been difficult to generate a neutral or adaptive explanation in part because the uricase enzyme evolved to become a pseudogene in apes thus masking typical signals of sequence evolution. Adding to the difficulty is a lack of clarity on the functional role of uric acid in apes. One popular hypothesis proposes that uric acid is a potent antioxidant that increased in concentration to compensate for the lack of vitamin C synthesis in primate species ∼65 Ma. Here, we have expanded on our previous work with resurrected ancient uricase proteins to better resolve the reshaping of uricase enzymatic activity prior to ape evolution. Our results suggest that the pivotal death-knell to uricase activity occurred between 20 and 30 Ma despite small sequential modifications to its catalytic efficiency for the tens of millions of years since primates lost their ability to synthesize vitamin C, and thus the two appear uncorrelated. We also use this opportunity to demonstrate how molecular evolution can contribute to biomedicine by presenting ancient uricases to human immune cells that assay for innate reactivity against foreign antigens. A highly stable and highly catalytic ancient uricase is shown to elicit a lower immune response in more human haplotypes than other uricases currently in therapeutic development.

Oral Delivery of Nanoparticles Carrying Ancestral Uricase Enzyme Protects against Hyperuricemia in Knockout Mice

“…The kinetic activity of Qβ@AncUOX was characterized by monitoring the disappearance of substrate uric acid. Michaelis–Menten treatment of initial-rate data (Figure a) gave a catalytic efficiency of approximately 2 × 10 5 M –1 s –1 per enzyme tetramer, similar to the approximately 5 × 10 5 M –1 s –1 value reported for unpackaged enzyme . Thus, the urate/uric acid is able to freely diffuse through the capsid shell and the catalytic power of the ancestral enzyme is not affected by sequestration in the VLP interior.…”

Diverse functions associate with non-coding polymorphisms shared between humans and chimpanzees

“…Uricase, the enzyme that metabolizes uric acid into an easily excreted water-soluble form in most mammals, has been lost in great apes. This gene was disabled by a series of mutations that slowly decreased activity over primate evolution, increasing the levels of uric acid in blood [ 45 , 46 ]. It has been hypothesized that this loss of uricase activity was driven by increase fructose in primate diets due to fruit eating [ 45 , 47 ].…”

The Purpose of Adrenarche Is Tumor Suppression: Identification of a Novel, Human-Specific, Kill-Switch Tumor Suppression Mechanism Dependent upon the Dramatic Adrenarchal Rise of Adrenal Androgens

“…For example, Uric acid was found to completely suppress benzo[a]pyrene quinone formation at a concentration significantly less than vitamin C [42]. Just as the purpose of adrenarche has been called "enigmatic," the purpose of high uric acid levels in higher primates has been termed "elusive" [43]. Thus, the question has been repeatedly asked, why would natural selection allow the accumulation of uric acid despite the physiological consequences of gout and liver and kidney damage?…”