Evolution of Uric Acid Metabolism in Humans

Bonifacio Alvarez‐Lario, Hospital Universitario de Burgos, Burgos, Spain
Jesús Macarrón‐Vicente, Hospital Universitario de Burgos, Burgos, Spain

Published online: January 2013

DOI: 10.1002/9780470015902.a0024618

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 (2011). © 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, 1979; Johnson et al., 2005, 2009; Zhu et al., 2011.
close
 References
    Alvarez-Lario B and Macarrón-Vicente J (2010) Uric acid and evolution. Rheumatology (Oxford) 49(11): 2010–2015.
    Alvarez-Lario B and Macarrón-Vicente J (2011) Is there anything good in uric acid? Quarterly Journal of Medicine 104(12): 1015–1024.
    Ames BN, Cathcart R, Schwiers E and Hochstein P (1981) Uric acid provides an antioxidant defense in human against oxidant- and radical-caused aging and cancer: a hypothesis. Proceedings of the National Academy of Sciences of the USA 78(11): 6858–6862.
    Andrews P (1992) Evolution and environment in the Hominoidea. Nature 360(6405): 641–646.
    Anzai N and Endou H (2011) Urate transporters: an evolving field. Seminars in Nephrology 31(5): 400–409.
    Boffeta P, Nordenvall C, Nyren O and Ye W (2009) A prospective study of gout and cancer. European Journal of Cancer Prevention 18(2): 127–132.
    Cahill GF Jr (1976) Starvation in man. Journal of Clinical Endocrinology and Metabolism 5(2): 397–415.
    Challet E, le Maho Y, Robin JP, Malan A and Cherel Y (1995) Involvement of corticosterone in the fasting-induced rise in protein utilization and locomotor activity. Pharmacology Biochemistry and Behavior 50(3): 405–412.
    Doherty M (2009) New insights into the epidemiology of gout. Rheumatology 48: ii2–ii8.
    Eaton SB and Konner M (1985) Paleolithic nutrition. New England Journal of Medicine 312(5): 283–289.
    Fainaru M and Schafer Z (2000) Effect of prolonged fasting on plasma lipids, lipoproteins and apolipoprotein B in 12 physicians participating in a hunger strike: an observational study. Israel Medical Association Journal 2(3): 215–219.
    Feig DI, Kang D-H and Johnson RJ (2008) Uric acid and cardiovascular risk. New England Journal of Medicine 359(17): 1811–1821.
    Forman JP, Choi H and Curhan GC (2007) Plasma uric acid level and risk for incident hypertension among men. Journal of the American Society of Nephrology 18(1): 287–292.
    Gao X, Curhan G, Forman JP, Ascherio A and Choi HK (2008) Vitamin C intake and serum uric acid concentration in men. Journal of Rheumatology 35(9): 1853–1858.
    Glantzounis GK, Tsimoyiannis EC, Kappas AM and Galaris DA (2005) Uric acid and oxidative stress. Current Pharmaceutical Design 11(32): 4145–4151.
    Hollis-Moffatt JE, Xu X, Dalbeth N et al. (2009) Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Maori, Pacific Island and Caucasian case-control sample sets. Arthritis and Rheumatism 60(11): 3485–3492.
    Houlihan LM, Wyatt ND, Harris SE et al. (2010) Variation in the uric acid transporter gene (SLC2A9) and memory performance. Human Molecular Genetics 19(11): 2321–2330.
    Huang HY, Appel LJ, Choi MJ et al. (2005) The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial. Arthritis and Rheumatism 52(6): 1843–1847.
    Ichida K (2009) What lies behind serum urate concentration? Insights from genetic and genomic studies. Genome Medicine 1(12): 118.1–118.10.
    Johnson RJ, Titte S, Cade JR, Rideout BA and Oliver WJ (2005) Uric acid, evolution and primitive cultures. Seminars in Nephrology 25(1): 3–8.
    Johnson RJ, Sautin YY, Oliver WJ et al. (2009) Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society? Journal of Comparative Physiology B 179(1): 67–76.
    Kolz M, Johnson T, Sanna S et al. (2009) Meta-analysis of 28,141 individuals identifies common variants within new loci that influence uric acid concentrations. PloS Genetics 5(6): e1000504.
    Kuo CF, See LC, Luo SF et al. (2010) Gout: an independent risk factor for all-cause and cardiovascular mortality. Rheumatology (Oxford) 49(1): 141–146.
    Kutzing MK and Firestein BL (2008) Altered uric acid levels and disease states. Journal of Pharmacology and Experimental Therapeutics 324(1): 1–7.
    Lai JY, Atzmon G, Melamed ML et al. (2012) Family history of exceptional longevity is associated with lower serum uric acid levels in Ashkenazi Jews. Journal of the American Geriatrics Society 60(4): 745–750.
    Lennox WG (1924) Increase of uric acid in the blood during prolonged starvation. Journal of the American Medical Association 82: 602.
    Linster CL and Van Schaftingen E (2007) Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS Journal 274(1): 1–22.
    Lipkowitz MS (2012) Regulation of uric acid excretion by the kidney. Current Rheumatology Reports 14(2): 179–188.
    Lloyd-Mostyn RH, Lord PS, Glover R, West C and Gilliland IC (1970) Uric acid metabolism in starvation. Annals of the Rheumatic Diseases 29(5): 553–555.
    Montoye HJ and Mikkelsen WM (1973) Serum uric acid and achievement in high school. Arthritis and Rheumatism 16(3): 359–362.
    Oda M, Satta Y, Takenaka O and Takahata N (2002) Loss of urate oxidase activity in hominoids and its evolutionary implications. Molecular Biology and Evolution 19(5): 640–653.
    Orowan E (1955) The origin of man. Nature 175(4459): 683–684.
    Pacher P, Beckman JS and Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiological Reviews 87(1): 315–424.
    Robin JP, Boucontet L, Chillet P and Groscolas R (1998) Behavioral changes in fasting emperor penguins: evidence for a “refeeding signal” linked to a metabolic shift. American Journal of Physiology 274(Pt 2): R746–R753.
    Roch-Ramel F (1979) Renal excretion of uric acid in mammals. Clinical Nephrology 12(1): 1–6.
    Saag KG and Choi H (2006) Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Research and Therapy 8(Suppl. 1): S2.
    Scott GS and Hooper DC (2001) The role of uric acid in protection against peroxynitrite-mediated pathology. Medical Hypotheses 56(1): 95–100.
    Sofaer JA and Emery AEH (1981) Genes for super-intelligence? Journal of Medical Genetics 18(6): 410–413.
    Strasak AM, Rapp K, Hilbe W et al. (2007) Serum uric acid and risk of cancer mortality in a large prospective male cohort. Cancer Causes and Control 18(9): 1021–1029.
    Varela-Echevarría A, Montes de Oca-Luna R and Barrera-Saldaña HA (1988) Uricase protein sequences: conserved during vertebrate evolution but absent in humans. FASEB Journal 2(15): 3092–3096.
    Watanabe S, Kang DH, Feng L et al. (2002) Uric acid, hominoid evolution and the pathogenesis of salt-sensitivity. Hypertension 40(3): 355–360.
    Wu XW, Muzny DM, Lee CC and Caskey CT (1992) Two independent mutational events in the loss of urate oxidase during hominoid evolution. Journal of Molecular Evolution 34(1): 78–84.
    Wu X, Wakamiya M, Vaishnav S et al. (1994) Hyperuricemia and urate nephropathy in urate oxidase-deficient mice. Proceedings of the National Academy of Sciences of the USA 91(2): 742–746.
    Zhu Y, Pandya BJ and Choi HK (2011) Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis and Rheumatism 63(10): 3136–3141.
 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.
    Chen X, Wu G and Schwarzschild MA (2012) Urate in Parkinson's disease: more than a biomarker? Current Neurology and Neuroscience Reports 12(4): 367–375.
    Konner M and Eaton SB (2010) Paleolithic nutrition: twenty-five years later. Nutrition in Clinical Practice 25(6): 594–602.
    Liu B, Shen Y, Xiao K et al. (2012) Serum uric acid levels in patients with multiple sclerosis: a meta-analysis. Journal of Neurology Research 34(2): 163–171.
    Riches PL, Wright AF and Ralston SH (2009) Recent insights into the pathogenesis of hyperuricemia and gout. Human Molecular Genetics 18: R177–R184.

Related Sub-Topics:

Molecular Evolution | Protein Evolution | Human Evolution
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Evolution of Uric Acid Metabolism in Humans
 
How to Cite close
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]