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To whom correspondence may be addressed. E-mail: eortlun@emory.edu, richard.johnson@ucdenver.edu, or eric.gaucher@biology.gatech.edu.

Author contributions: J.T.K., M.A.L., M.N.M., E.A.O., R.J.J., and E.A.G. designed research; J.T.K., M.A.L., M.N.M., C.C., C.L.G., and E.A.G. performed research; J.T.K., M.A.L., M.N.M., P.A.T., E.A.O., R.J.J., and E.A.G. analyzed data; and J.T.K., M.A.L., E.A.O., R.J.J., and E.A.G. wrote the paper.

Acknowledgments We thank Betül Kaçar, Valery Adorno-Cruz, and Laura O’Farrell for their assistance. This work was supported by Technological Innovation: Generating Economic Results (TI:GER), Graduate Assistance in Areas of National Need (GAANN), and Translational Research Institute for Biomedical Engineering and Science (TRIBES) programs at the Georgia Institute of Technology (J.T.K.), the Georgia Research Alliance (E.A.G.), and start-up funds from the Georgia Institute of Technology (E.A.G.), University of Colorado (R.J.J.), and Emory University (E.A.O.). Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38.

Conflict of interest statement: E.A.G. declares financial interest because a patent related to this research has been filed by the Georgia Institute of Technology, and this technology is licensed to General Genomics, LLC, which is a start-up founded by E.A.G.. R.J.J. is an inventor on several patents and patent applications related to lowering uric acid as a means for treating hypertension, diabetic nephropathy, and renal disease, and is a founder of XORT, Inc., which is a start-up company that has licensed these applications.

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Research Funding:

This work was supported by Technological Innovation: Generating Economic Results (TI:GER), Graduate Assistance in Areas of National Need (GAANN), and Translational Research Institute for Biomedical Engineering and Science (TRIBES) programs at the Georgia Institute of Technology (J.T.K.), the Georgia Research Alliance (E.A.G.), and start-up funds from the Georgia Institute of Technology (E.A.G.), University of Colorado (R.J.J.), and Emory University (E.A.O.).

Keywords:

  • hyperuricemia
  • pseudogene
  • evolution

Evolutionary history and metabolic insights of ancient mammalian uricases

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Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 111, Number 10

Publisher:

, Pages 3763-3768

Type of Work:

Article | Final Publisher PDF

Abstract:

Uricase is an enzyme involved in purine catabolism and is found in all three domains of life. Curiously, uricase is not functional in some organisms despite its role in converting highly insoluble uric acid into 5-hydroxyisourate. Of particular interest is the observation that apes, including humans, cannot oxidize uric acid, and it appears that multiple, independent evolutionary events led to the silencing or pseudogenization of the uricase gene in ancestral apes. Various arguments have been made to suggest why natural selection would allow the accumulation of uric acid despite the physiological consequences of crystallized monosodium urate acutely causing liver/kidney damage or chronically causing gout. We have applied evolutionary models to understand the history of primate uricases by resurrecting ancestral mammalian intermediates before the pseudogenization events of this gene family. Resurrected proteins reveal that ancestral uricases have steadily decreased in activity since the last common ancestor of mammals gave rise to descendent primate lineages. We were also able to determine the 3D distribution of amino acid replacements as they accumulated during evolutionary history by crystallizing a mammalian uricase protein. Further, ancient and modern uricases were stably transfected into HepG2 liver cells to test one hypothesis that uricase pseudogenization allowed ancient frugivorous apes to rapidly convert fructose into fat. Finally, pharmacokinetics of an ancient uricase injected in rodents suggest that our integrated approach provides the foundation for an evolutionarily-engineered enzyme capable of treating gout and preventing tumor lysis syndrome in human patients.

Copyright information:

© 2014 National Academy of Sciences.

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