A reductive uric acid degradation pathway in anaerobic bacteria

Abstract Uric acid (UA) is a key intermediate in purine degradation across diverse organisms, while its accumulation in humans leads to inflammation and gout disease. Aerobic organisms degrade UA via a well-known “oxidative pathway” involving dearomatization of the purine core catalyzed by UA oxidases or dehydrogenases. The ability to degrade UA is also widespread in anaerobic bacteria, including gut bacteria, although the mechanisms are incompletely understood. Here, we report the biochemical characterization of a recently identified UA degradation gene cluster from Escherichia coli, and show that it encodes a “reductive pathway” for UA degradation. In this pathway, UA is first reduced to 2,8-dioxopurine (yanthine) by a xanthine dehydrogenase homolog (XdhD), followed by dearomatization of the purine core catalyzed by a flavin-dependent reductase (YgfK). Stepwise cleavage of the pyrimidine and imidazole rings forms 2,3-diureidopropionate, and stepwise cleavage of the 2- and 3-ureido groups then forms 2,3-diaminopropionate, which is cleaved by a pyridoxal 5’-phosphate-dependent lyase (YgeX) to pyruvate and ammonia. The detection of yanthine in clinical serum samples from healthy individuals and significantly higher levels from gout patients suggests that yanthine is a physiologically relevant circulating metabolite. A probiotic E. coli Nissle strain was engineered for constitutive overexpression of the gene cluster, and oral administration in a uricase-knockout hyperuricemic mouse model significantly reduced the serum UA level and alleviated associated kidney injury, suggesting a potential route towards uricolytic probiotics.