Vertebrate HIU hydrolase: Identification, function, structure and evolutionary relationship with transthyretin

5-hydroxyisourate hydrolase (HIUase) is an enzyme widely distributed in prokaryotic and eukaryotic organisms that catalyzes the hydrolysis of HIU into OHCU in the degradation route from urate to (S)-allantoin. During early vertebrate evolution, a duplication event in the gene encoding HIUase gave rise to the thyroid hormone binding protein transthyretin (TTR). Due to the close evolutionary relationship between HIUase and TTR, these two proteins possess a high 2 degree of amino acid sequence similarity, while performing quite different functions. The 3D structure of zebrafish HIUase compares very well with that of TTR: a highly preserved scaffold harbors distinct functional sites located in the same regions of the two proteins. The residues that are differentially conserved in HIUase as compared to TTR map in catalytic regions occupying the outer portions of the two halves of the central channel that transverses the whole tetrameric proteins. The evolution of HIUase into TTR has been accompanied by remarkable changes of the catalytic sites to give rise to a channel open at both ends, thus allowing free access to hormone molecules.