title: Catalytic mechanism of yeast cytosine deaminase: an ONIOM computational study.
abstract: The complete path for the deamination reaction catalyzed by yeast cytosine deaminase (yCD), a zinc metalloenzyme of significant biomedical interest, has been investigated using the ONIOM method. Cytosine deamination proceeds via a sequential mechanism involving the protonation of N(3), the nucleophilic attack of C(4) by the zinc-coordinated hydroxide, and the cleavage of the C(4)-N(4) bond. The last step is the rate determining step for the generation of the zinc bound uracil. Uracil is liberated from the Zn atom by an oxygen exchange mechanism that involves the formation of a gem-diol intermediate from the Zn bound uracil and a water molecule, the C(4)-O(Zn) cleavage, and the regeneration of the Zn-coordinated water. The rate determining step in the oxygen exchange is the formation of the gem-diol intermediate, which is also the rate determining step for the overall yCD-catalyzed deamination reaction.
authors.affiliation: Center for Biological Modeling and Departments of Biochemistry and Chemistry, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Stepan
authors.initials: S
authors.lastname: Sklenak
authors.forename: Lishan
authors.initials: L
authors.lastname: Yao
authors.forename: Robert I
authors.initials: RI
authors.lastname: Cukier
authors.forename: Honggao
authors.initials: H
authors.lastname: Yan
mesh_terms: D002384:Catalysis; D043525:Cytosine Deaminase / Q000737:chemistry* / Q000378:metabolism*; D003641:Deamination; D004926:Escherichia coli / Q000201:enzymology; D007700:Kinetics; D008958:Models, Molecular; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013816:Thermodynamics; D015003:Yeasts / Q000201:enzymology*
chemical_list: D043525:Cytosine Deaminase; D010100:Oxygen