The Role of Uric Acid in Human Health: Insights from the Uricase Gene

Abstract

Uric acid is the final product of purine metabolism and is converted to allantoin in most mammals via the uricase enzyme. The accumulation of loss of function mutations in the uricase gene rendered hominoids (apes and humans) to have higher urate concentrations compared to other mammals. The loss of human uricase activity may have allowed humans to survive environmental stressors, evolution bottlenecks, and life-threatening pathogens. While high urate levels may contribute to developing gout and cardiometabolic disorders such as hypertension and insulin resistance, low urate levels may increase the risk for neurodegenerative diseases. The double-edged sword effect of uric acid has resurrected a growing interest in urate’s antioxidant role and the uricase enzyme’s role in modulating the risk of obesity. Characterizing both the effect of uric acid levels and the uricase enzyme in different animal models may provide new insights into the potential therapeutic benefits of uric acid and novel uricase-based therapy.

Emerging Roles of Xanthine Oxidoreductase in Chronic Kidney Disease

“…Allantoin results from a ring-opening oxidation of the purine skeleton at the C-2 position, which improves water solubility. Animals with UOX improve renal elimination of products of purine catabolism compared to humans who lack UOX which can accumulate pathological levels of UA [ 32 ].…”

Uric acid‐lowering effects of sodium‐glucose cotransporter 2 inhibitors for preventing cardiovascular events and mortality: A systematic review and meta‐analysis

“…[1][2][3][4] On the other hand, it has been proposed that the retention of UA represents an adaptive mechanism for human survival. 5 Indeed, the high UA blood levels observed in humans, in contrast to most other mammals, may have been an adaptive mechanism providing antioxidant capacity in situations of low availability of fruits and vegetables, 6 with UA accounting for about 50%-60% of antioxidants naturally present in humans. 7 Regarding clinical events, a U-shaped association of UA to cardiovascular events and all-cause mortality has been shown.…”

“…Numerous large epidemiological studies and their meta‐analyses have repeatedly shown a strong association between serum urate levels and several cardiovascular and metabolic disorders and risk factors 1–4 . On the other hand, it has been proposed that the retention of UA represents an adaptive mechanism for human survival 5 . Indeed, the high UA blood levels observed in humans, in contrast to most other mammals, may have been an adaptive mechanism providing antioxidant capacity in situations of low availability of fruits and vegetables, 6 with UA accounting for about 50%‐60% of antioxidants naturally present in humans 7 .…”