The merits of bipartite transition-state mimics for inhibition of uracil DNA glycosylase

The glycosidic bond hydrolysis reaction of the enzyme uracil DNA glycosylase (UDG) occurs by a two-step mechanism involving complete bond breakage to the uracil anion leaving group in the first step, formation of a discrete glycosyl cation-uracil anion intermediate, followed by water attack in a sec...

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Bibliographic Details
Published in:Bioorganic chemistry 2004-08, Vol.32 (4), p.244-262
Main Authors: Jiang, Yu Lin, Cao, Chunyang, Stivers, James T., Song, Fenhong, Ichikawa, Yoshi
Format: Article
Language:English
Subjects:
1-Azadeoxyribose
Amides
Binding, Competitive
DNA Glycosylases - antagonists & inhibitors
DNA Repair
Enzyme inhibition
Enzyme Inhibitors - chemical synthesis
Escherichia coli Proteins - antagonists & inhibitors
Hydrogen-Ion Concentration
Molecular Mimicry
Oligonucleotides - chemical synthesis
Oligonucleotides - pharmacology
Phosphoric Acids
Structure-Activity Relationship
Transition-state mimics
Uracil DNA glycosylase
Uracil-DNA Glycosidase
Uridine - analogs & derivatives
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Summary:The glycosidic bond hydrolysis reaction of the enzyme uracil DNA glycosylase (UDG) occurs by a two-step mechanism involving complete bond breakage to the uracil anion leaving group in the first step, formation of a discrete glycosyl cation-uracil anion intermediate, followed by water attack in a second transition-state leading to the enzyme-bound products of uracil and abasic DNA. We have synthesized and determined the binding affinities of unimolecular mimics of the substrate and first transition-state (TS1) in which the uracil base is covalently attached to the sugar, and in addition, bimolecular mimics of the second addition transition state (TS2) in which the base and sugar are detached. We find that the bipartite mimics of TS2 are superior to the TS1 mimics. These results indicate that bipartite TS2 inhibitors could be useful for inhibition of glycosylases that proceed by stepwise reaction mechanisms.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2004.03.001