Saturday, April 20, 2024
4/20/2024
¿ DESCRIPTION (provided by applicant) Highly insoluble urate in the human body leads to both gouty arthritis and renal damage. Humans (and some other species) are uniquely susceptible to urate because we do not synthesize a functional uricase enzyme responsible for converting insoluble urate to more soluble molecules that can be easily excreted from the body. Crystallization during urate build- up causes both severe inflammation in the distal joints and kidney malfunction. Despite its clinical relevance, little is known about how or why the enzymes and transporters that produce and relocate urate in the body evolved in primates. For instance, why do humans not have an active uricase enzyme? Did other components of the urate pathway co-adapt to the loss of functional uricase? We will apply evolutionary analyses to reveal the molecular paths that shaped the evolution of gene families responsible for urate metabolism. Our research focuses on uricase, xanthine oxidoreductase and urate transporter-1 proteins from both modern and ancient organisms. Research will consist of sequencing these genes from modern organisms, inferring and synthesizing ancestral forms of these genes, and performing biochemical and cellular assays in order to reveal how the functions of these proteins have changed during evolutionary history. This multidisciplinary approach will expand our basic understanding of enzyme evolution and metabolic co-adaptation, and allow us to improve uricase therapeutics. Current uricase therapeutics are highly limiting due to poor solubility at plasma pH and strong immunogenicity when presented to human patients. Our preliminary data demonstrate that particular ancient uricases are substantially more soluble in rodent models and less immunogenic when presented to activated human T-cells. We are confident that our novel uricases will lead the development of next-generation therapeutics that treat gout and prevent tumor lysis syndrome.
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