5M98

Crystal structure of urate oxidase from zebrafish

5M98 の概要

• エントリーDOI: 10.2210/pdb5m98/pdb
• 分子名称: Uricase (2 entities in total)
• 機能のキーワード: uric acid, urate, purine metabolism, uricolytic activities, oxidoreductase
• 由来する生物種: Danio rerio (Zebrafish)
• 細胞内の位置: Peroxisome : Q6DG85
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 273913.90

構造登録者

Zanotti, G.,Cendron, l.,Percudani, R.,Berni, R. (登録日: 2016-11-01, 公開日: 2016-12-21, 最終更新日: 2024-11-13)

主引用文献

Marchetti, M.,Liuzzi, A.,Fermi, B.,Corsini, R.,Folli, C.,Speranzini, V.,Gandolfi, F.,Bettati, S.,Ronda, L.,Cendron, L.,Berni, R.,Zanotti, G.,Percudani, R.
Catalysis and Structure of Zebrafish Urate Oxidase Provide Insights into the Origin of Hyperuricemia in Hominoids.
Sci Rep, 6:38302-38302, 2016

PubMed Abstract: Urate oxidase (Uox) catalyses the first reaction of oxidative uricolysis, a three-step enzymatic pathway that allows some animals to eliminate purine nitrogen through a water-soluble compound. Inactivation of the pathway in hominoids leads to elevated levels of sparingly soluble urate and puts humans at risk of hyperuricemia and gout. The uricolytic activities lost during evolution can be replaced by enzyme therapy. Here we report on the functional and structural characterization of Uox from zebrafish and the effects on the enzyme of the missense mutation (F216S) that preceded Uox pseudogenization in hominoids. Using a kinetic assay based on the enzymatic suppression of the spectroscopic interference of the Uox reaction product, we found that the F216S mutant has the same turnover number of the wild-type enzyme but a much-reduced affinity for the urate substrate and xanthine inhibitor. Our results indicate that the last functioning Uox in hominoid evolution had an increased Michaelis constant, possibly near to upper end of the normal range of urate in the human serum (~300 μM). Changes in the renal handling of urate during primate evolution can explain the genetic modification of uricolytic activities in the hominoid lineage without the need of assuming fixation of deleterious mutations.

PubMed: 27922051
DOI: 10.1038/srep38302

実験手法

X-RAY DIFFRACTION (2.8 Å)