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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
21
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pubmed:dateCreated |
2003-5-19
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pubmed:databankReference |
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pubmed:abstractText |
Yeast cytosine deaminase is an attractive candidate for anticancer gene therapy because it catalyzes the deamination of the prodrug 5-fluorocytosine to form 5-fluorouracil. We report here the crystal structure of the enzyme in complex with the inhibitor 2-hydroxypyrimidine at 1.6-A resolution. The protein forms a tightly packed dimer with an extensive interface of 1450 A2 per monomer. The inhibitor was converted into a hydrated adduct as a transition-state analog. The essential zinc ion is ligated by the 4-hydroxyl group of the inhibitor together with His62, Cys91, and Cys94 from the protein. The enzyme shares similar active-site architecture to cytidine deaminases and an unusually high structural homology to 5-aminoimidazole-4-carboxamide-ribonucleotide transformylase and thereby may define a new superfamily. The unique C-terminal tail is involved in substrate specificity and also functions as a gate controlling access to the active site. The complex structure reveals a closed conformation, suggesting that substrate binding seals the active-site entrance so that the catalytic groups are sequestered from solvent. A comparison of the crystal structures of the bacterial and fungal cytosine deaminases provides an elegant example of convergent evolution, where starting from unrelated ancestral proteins, the same metal-assisted deamination is achieved through opposite chiral intermediates within distinctly different active sites.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
23
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
19111-7
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:12637534-Amino Acid Sequence,
pubmed-meshheading:12637534-Antineoplastic Agents,
pubmed-meshheading:12637534-Binding Sites,
pubmed-meshheading:12637534-Catalysis,
pubmed-meshheading:12637534-Crystallization,
pubmed-meshheading:12637534-Cytosine Deaminase,
pubmed-meshheading:12637534-Dimerization,
pubmed-meshheading:12637534-Enzyme Inhibitors,
pubmed-meshheading:12637534-Escherichia coli,
pubmed-meshheading:12637534-Evolution, Molecular,
pubmed-meshheading:12637534-Flucytosine,
pubmed-meshheading:12637534-Fluorouracil,
pubmed-meshheading:12637534-Hydrogen Bonding,
pubmed-meshheading:12637534-Models, Molecular,
pubmed-meshheading:12637534-Molecular Sequence Data,
pubmed-meshheading:12637534-Molecular Structure,
pubmed-meshheading:12637534-Nucleoside Deaminases,
pubmed-meshheading:12637534-Pyrimidines,
pubmed-meshheading:12637534-Saccharomyces cerevisiae,
pubmed-meshheading:12637534-Sequence Alignment,
pubmed-meshheading:12637534-Stereoisomerism,
pubmed-meshheading:12637534-Substrate Specificity
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pubmed:year |
2003
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pubmed:articleTitle |
Crystal structure of yeast cytosine deaminase. Insights into enzyme mechanism and evolution.
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pubmed:affiliation |
Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, Non-U.S. Gov't
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