Structure of Zebra fish HIUase: Insights into Evolution of an Enzyme to a Hormone Transporter

Zanotti, Giuseppe; Cendron, Laura; Ramazzina, Ileana; Folli, Claudia; Percudani, Riccardo; Berni, Rodolfo

doi:10.1016/j.jmb.2006.07.079

Cited by 51 publications

(63 citation statements)

References 28 publications

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“…(S)-Allantoin used in the CD assays was produced through the degradation of uric acid (0.2 mM) in the presence of 0.16 units of urate oxidase from Candida utilis, 0.12 g of zebrafish 5-hydroxyisourate hydrolase (23), and 6 g of zebrafish OHCU decarboxylase (6). The reactions were conducted in 1 ml of 0.1 M potassium phosphate, pH 7.6.…”

Section: Methodsmentioning

confidence: 99%

Logical Identification of an Allantoinase Analog (puuE) Recruited from Polysaccharide Deacetylases

Ramazzina

Cendron

Folli

et al. 2008

Journal of Biological Chemistry

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The hydrolytic cleavage of the hydantoin ring of allantoin, catalyzed by allantoinase, is required for the utilization of the nitrogen present in purine-derived compounds. The allantoinase gene (DAL1), however, is missing in many completely sequenced organisms able to use allantoin as a nitrogen source. Here we show that an alternative allantoinase gene (puuE) can be precisely identified by analyzing its logic relationship with three other genes of the pathway. The novel allantoinase is annotated in structure and sequence data bases as polysaccharide deacetylase for its homology with enzymes that catalyze hydrolytic reactions on chitin or peptidoglycan substrates. The recombinant PuuE protein from Pseudomonas fluorescens exhibits metal-independent allantoinase activity and stereospecificity for the S enantiomer of allantoin. The crystal structures of the protein and of protein-inhibitor complexes reveal an overall similarity with the polysaccharide deacetylase ␤/␣ barrel and remarkable differences in oligomeric assembly and active site geometry. The conserved Asp-His-His metalbinding triad is replaced by Glu-His-Trp, a configuration that is distinctive of PuuE proteins within the protein family. An extra domain at the top of the barrel offers a scaffold for protein tetramerization and forms a small substrate-binding cleft by hiding the large binding groove of polysaccharide deacetylases. Substrate positioning at the active site suggests an acid/base mechanism of catalysis in which only one member of the catalytic pair of polysaccharide deacetylases has been conserved. These data provide a structural rationale for the shifting of substrate specificity that occurred during evolution.

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Section: Methodsmentioning

confidence: 99%

Logical Identification of an Allantoinase Analog (puuE) Recruited from Polysaccharide Deacetylases

Ramazzina

Cendron

Folli

et al. 2008

Journal of Biological Chemistry

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“…S1B), suggesting that this residue may be important for normal protein function. Crystal structures of HIU hydrolase from prokaryotes as well as zebra fish (13)(14)(15) predict that the tyrosine substituted in Urah plt2/plt2 mice (Y98) normally exists in a highly structured helical region and forms a strong set of hydrophobic interactions between the helix and adjacent β-sheet strands (Fig. S1C).…”

Section: Platelet 2 An Enu-induced Mutation Causing Thrombocytosis Andmentioning

confidence: 99%

“…S1C). Although not part of the predicted active site at the interface between the subunits of the HIU hydrolase tetramer (13)(14)(15), replacement of the aromatic tyrosine residue with a sulfur-containing cysteine in the Urah Plt2 protein is likely to disrupt this highly ordered hydrophobic core and lead to protein instability.…”

Section: Platelet 2 An Enu-induced Mutation Causing Thrombocytosis Andmentioning

confidence: 99%

Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice

Stevenson

Hyland²,

Zhang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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With the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5-hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase in most vertebrate species. A point mutation in the gene encoding mouse HIU hydrolase, Urah, that perturbed uric acid metabolism within the liver was discovered during a mutagenesis screen in mice. The predicted substitution of cysteine for tyrosine in a conserved helical region of the mutantencoded HIU hydrolase resulted in undetectable protein expression. Mice homozygous for this mutation developed elevated platelet counts secondary to excess thrombopoietin production and hepatomegaly. The majority of homozygous mutant mice also developed hepatocellular carcinoma, and tumor development was accelerated by exposure to radiation. The development of hepatomegaly and liver tumors in mice lacking Urah suggests that uric acid metabolites may be toxic and that urate oxidase activity without HIU hydrolase function may affect liver growth and transformation. The absence of HIU hydrolase in humans predicts slowed metabolism of HIU after clinical administration of exogenous urate oxidase in conditions of uric acid-related pathology. The data suggest that prolonged urate oxidase therapy should be combined with careful assessment of toxicity associated with extrahepatic production of uric acid metabolites.N-ethyl-N-nitrosourea mutagenesis | uric acid | 5-hydroxyisourate hydrolase | hepatocellular carcinoma | thrombopoietin U ric acid is the product of purine metabolism. In most mammals, uric acid, or urate, the form that predominates in vivo, is further metabolized to (S)-allantoin (1, 2). In humans and some higher primates, the urate oxidase gene is dysfunctional because of the introduction of premature stop codons during recent evolution (3). A nonfunctional urate oxidase enzyme causes a relative excess of uric acid in humans compared with most other vertebrate species. Because uric acid is relatively insoluble, humans are susceptible to diseases resulting from precipitation of uric acid such as gout and kidney stones as well as urate nephropathy associated with the tumor lysis syndrome. Chronic hyperuricemia in humans has also been linked to the development of cardiovascular disease and hypertension (4, 5).It is unclear why humans have evolved this block in uric acid metabolism during evolution, but suggested theoretical advantages of increased levels of circulating uric acid include its role as a potent antioxidant offering protection from cancer and aging (6) and its potential function in maintenance of adequate blood pressure during periods of low salt intake (7).The components of the full metabolic pathway that converts urate to allantoin in lower mammals have only recently been identified (1). Although it was originally thought that urate oxidase was the sole enzymatic component of this pathway, recent studies have established that conversion of uric acid to allantoin occurs by sequential ch...

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“…Finally, a gene coding for OHCU decarboxylase (urad) has been found to be required for the stereoselective formation of S-allantoin . Remarkably, it has been shown that the thyroid hormone transporter transthyretin originated in vertebrates by duplication of the urah gene (Zanotti et al, 2006). Such a finding implies that very different roles, such as enzymatic activities and hormone transport, can be accomplished by proteins containing the HIUase fold.…”

Section: Introductionmentioning

confidence: 99%

Conserved Alternative Splicing of Arabidopsis Transthyretin-Like Determines Protein Localization and S-Allantoin Synthesis in Peroxisomes

et al. 2010

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S-allantoin, a major ureide compound, is produced in plant peroxisomes from oxidized purines. Sequence evidence suggested that the Transthyretin-like (TTL) protein, which interacts with brassinosteroid receptors, may act as a bifunctional enzyme in the synthesis of S-allantoin. Here, we show that recombinant TTL from Arabidopsis thaliana catalyzes two enzymatic reactions leading to the stereoselective formation of S-allantoin, hydrolysis of hydroxyisourate through a C-terminal Urah domain, and decarboxylation of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline through an N-terminal Urad domain. We found that two different mRNAs are produced from the TTL gene through alternative use of two splice acceptor sites. The corresponding proteins differ in the presence (TTL 12 ) and the absence (TTL 22 ) of a rare internal peroxisomal targeting signal (PTS2). The two proteins have similar catalytic activity in vitro but different in vivo localization: TTL 12 localizes in peroxisomes, whereas TTL 22 localizes in the cytosol. Similar splice variants are present in monocots and dicots. TTL originated in green algae through a Urad-Urah fusion, which entrapped an N-terminal PTS2 between the two domains. The presence of this gene in all Viridiplantae indicates that S-allantoin biosynthesis has general significance in plant nitrogen metabolism, while conservation of alternative splicing suggests that this mechanism has general implications in the regulation of the ureide pathway in flowering plants.

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Structure of Zebra fish HIUase: Insights into Evolution of an Enzyme to a Hormone Transporter

Cited by 51 publications

References 28 publications

Logical Identification of an Allantoinase Analog (puuE) Recruited from Polysaccharide Deacetylases

Logical Identification of an Allantoinase Analog (puuE) Recruited from Polysaccharide Deacetylases

Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice

Conserved Alternative Splicing of Arabidopsis Transthyretin-Like Determines Protein Localization and S-Allantoin Synthesis in Peroxisomes

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