4MB8

Evolutionary history and metabolic insights of ancient mammalian uricases

4MB8 の概要

• エントリーDOI: 10.2210/pdb4mb8/pdb
• 分子名称: Uricase, ACETATE ION (3 entities in total)
• 機能のキーワード: uric acid oxidase, lysozome, oxidoreductase
• 由来する生物種: unclassified Mammalia
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 140461.90

構造登録者

Ortlund, E.O.,Murphy, M.N. (登録日: 2013-08-19, 公開日: 2014-02-05, 最終更新日: 2024-02-28)

主引用文献

Kratzer, J.T.,Lanaspa, M.A.,Murphy, M.N.,Cicerchi, C.,Graves, C.L.,Tipton, P.A.,Ortlund, E.A.,Johnson, R.J.,Gaucher, E.A.
Evolutionary history and metabolic insights of ancient mammalian uricases.
Proc.Natl.Acad.Sci.USA, 111:3763-3768, 2014

PubMed 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.

PubMed: 24550457
DOI: 10.1073/pnas.1320393111

実験手法

X-RAY DIFFRACTION (2.4009 Å)