Evolution of Uric Acid Metabolism in Humans


Several evolutionary changes have led to uric acid levels being much higher in humans than in other mammals. Uric acid is the end product of purine metabolism in hominoids, including humans, due to the genetic loss of uricase activity during the Miocene epoch, and this is the main cause of the increased uric acid in hominoids. Additional factors that have contributed to increased levels of uric acid are the high renal tubular reabsorption of uric acid and the previous loss of the ability to synthesise vitamin C in hominoids. Several hypotheses have been proposed on the evolutionary advantage of increased serum uric acid levels in hominoids, although the biological reasons for this increase remain unclear. The large current increase in uric acid levels in humans in developed countries is mainly influenced by dietary factors and lifestyle changes.

Key Concepts:

  • Uric acid (UA) is the end product of purine metabolism in humans due to the loss of uricase activity by various mutations of its gene during the Miocene epoch.

  • Loss of uricase activity led to humans having higher UA levels than other mammals.

  • The high renal tubular reabsorption of UA and the previous loss of the ability to synthesise vitamin C may have also contributed to increased levels of UA in humans.

  • The biological reason for the loss of uricase activity and increased levels of UA in humans and certain primates is unknown.

  • UA is one of the most important antioxidants in human biological fluids.

  • UA probably has neuroprotective activity.

  • The current large increase in UA levels in humans in developed countries is mainly influenced by eating habits and lifestyle changes.

  • Hyperuricaemia can cause gout and uric lithiasis, and is associated with hypertension, metabolic syndrome, renal disease and cardiovascular disease.

Keywords: uric acid; gout; hyperuricaemia; uricase; urate oxidase; vitamin C; urate transporter; evolution; neuroprotective effect; diet

Figure 1.

Schematic diagram of purine metabolism. The majority of mammals have very low serum urate levels because UA is converted by uricase (also called urate oxidase) to allantoin, a very soluble excretion product, which is freely eliminated in the urine. The allantoin in most fish and amphibians is degraded via allantoic acid by allantoinase and allantoicase to urea and glyoxylate. In some marine invertebrates and crustaceans, the urea formed is hydrolysed to ammonia by urease. AMP: adenosine monophosphate; IMP: inosine monophosphate; GMP: guanosine monophosphate. Reproduced with permission from Alvarez‐Lario and Macarrón‐Vicente . © Oxford University Press.

Figure 2.

Cladrogram of hominoid evolution and the various mutations of uricase gene observed. Reproduced from Satta Y (2011) Primate Evolution: Gene Loss and Inactivation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net (doi:10.1002/9780470015902.a0005121.pub2).

Figure 3.

Schematic representation of urate renal transport in the proximal tubule. Less than 5% of UA circulates bound to proteins; therefore practically 100% is filtered in the glomeruli. Urate reabsorption dominates over secretion, resulting in the reabsorption of 90% and excretion of approximately 10% of its filtered load at the glomerulus. Urate reabsorption in human proximal tubules is performed mainly by the exchanger URAT1 (encoded by SLC22A12) and facilitator GLUT9 (SLC2A9) in tandem. In addition, other transporters such as OAT4 (SLC22A11) and OAT10 (SLC22A13) have been proposed to function in urate reabsorption. Urate secretion in human proximal tubules is performed mainly by exchangers OAT1 (SLC22A6) and/or OAT3 (SLC22A8) and facilitators NPT1 (SLC17A1) and NPT4 (SLC17A3). In addition, MRP4 (ABCC4) and BCRP (ABCG2) are proposed to function in urate secretion.

Figure 4.

Chemical structure of uric acid, caffeine and theobromine.

Figure 5.

Serum UA concentration in different mammals. Values for mean UA were obtained from Roch‐Ramel, ; Johnson et al., ; Zhu et al., .



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Further Reading

Anzai N, Jutabha P, Amonpatumrat‐Takahashi S and Sakurai H (2012) Recent advances in renal urate transport: characterization of candidate transporters indicated by genome‐wide association studies. Clinical and Experimental Nephrology 16(1): 89–95.

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Riches PL, Wright AF and Ralston SH (2009) Recent insights into the pathogenesis of hyperuricemia and gout. Human Molecular Genetics 18: R177–R184.

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Alvarez‐Lario, Bonifacio, and Macarrón‐Vicente, Jesús(Jan 2013) Evolution of Uric Acid Metabolism in Humans. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024618]