ArticleMolecular biology and evolution2016
Coevolution of URAT1 and Uricase during Primate Evolution: Implications for Serum Urate Homeostasis and Gout.
Article in Molecular biology and evolution, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 83 citations in OpenAlex.
- Therapeutic Strategies for Hyperuricemia: From Small-Molecule Inhibitors to RNA Therapeutics.ACS pharmacology & translational science · 2026Review
- SLC52A1 is a neofunctionalized primate urate transporter enabling intestinal urate secretion.The Journal of biological chemistry · 2026Article
- Inverted U-Shaped Association Between Serum Uric Acid and Handgrip Strength in Chinese Community-Dwelling Adults: A Repeated-Measures Cohort Study.Biomedicines · 2026Article
- Urinary phytoestrogen metabolites are associated with a reduced risk of hyperuricemia.Clinical rheumatology · 2026Article
- A review of the evidence for a protective role of uric acid in Parkinson's disease.NPJ Parkinson's disease · 2025Review
- Designer probiotic-based living drugs for uric acid homeostasis control in hyperuricemic mice and rats.Cell reports. Medicine · 2025Article
- Genomic insertion of ancestral uricase into human liver cells to determine metabolic consequences of pseudogenization.Scientific reports · 2025Article
- Molecular mechanism of drug inhibition of URAT1.Nature communications · 2025Article
- The Impact of Hyperuricemia on Pharmacokinetics in Sprague-Dawley Rats.European journal of drug metabolism and pharmacokinetics · 2025Article
- Unraveling the impact of miRNAs on gouty arthritis: diagnostic significance and therapeutic opportunities.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- The impact of serum uric acid on biological aging and mortality risk: insights from the NHANES and CHARLS cohorts.Frontiers in nutrition · 2025Article
- Transport mechanism and structural pharmacology of human urate transporter URAT1.Cell research · 2024Article
- Investigating metabolic dysregulation in serum of triple transgenic Alzheimer's disease male mice: implications for pathogenesis and potential biomarkers.Amino acids · 2024Article
- The NLRP3 inflammasome: role in the pathobiology of chronic pain.Inflammopharmacology · 2023Review
- Oral Delivery of Nanoparticles Carrying Ancestral Uricase Enzyme Protects against Hyperuricemia in Knockout Mice.Biomacromolecules · 2023Article
- Randomized, Double-Blind, Placebo-Controlled, Phase I, Dose- Escalation Study to Evaluate the Tolerance, Pharmacokinetics, Pharmacodynamics and Immunogenicity of PEGylated Urate Oxidase for Injection in Healthy Adults and Hyperuricemia Volunteers: Study Protocol.Diabetes, metabolic syndrome and obesity : targets and therapy · 2023Article
- Bearing Fruit: Miocene Apes and Rosaceous Fruit Evolution.Biological theory · 2023Article
- Anti-hyperuricemia effect of hesperetin is mediated by inhibiting the activity of xanthine oxidase and promoting excretion of uric acid.Frontiers in pharmacology · 2023Article
- Hormesis and Oxidative Distress: Pathophysiology of Reactive Oxygen Species and the Open Question of Antioxidant Modulation and Supplementation.Antioxidants (Basel, Switzerland) · 2022Review
- Acute oral toxicity assessment and anti-hyperuricemic activity ofSaudi journal of biological sciences · 2022Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Uric acid is the highly insoluble end-product of purine metabolism in humans. Serum levels exceeding the solubility threshold can trigger formation of urate crystals resulting in gouty arthritis. Uric acid is primarily excreted through the kidneys with 90% reabsorbed back into the bloodstream through the uric acid transporter URAT1. This reabsorption process is essential for the high serum uric acid levels found in humans. We discovered that URAT1 proteins from humans and baboons have higher affinity for uric acid compared with transporters from rats and mice. This difference in transport kinetics of URAT1 orthologs, along with inability of modern apes to oxidize uric acid due to loss of the uricase enzyme, prompted us to ask whether these events occurred concomitantly during primate evolution. Ancestral URAT1 sequences were computationally inferred and ancient transporters were resurrected and assayed, revealing that affinity for uric acid was increased during the evolution of primates. This molecular fine-tuning occurred between the origins of simians and their diversification into New- and Old-World monkey and ape lineages. Remarkably, it was driven in large-part by only a few amino acid replacements within the transporter. This alteration in primate URAT1 coincided with changes in uricase that greatly diminished the enzymatic activity and took place 27-77 Ma. These results suggest that the modifications to URAT1 transporters were potentially adaptive and that maintaining more constant, high levels of serum uric acid may have provided an advantage to our primate ancestors.
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