PMID:15210339

Citation	Jiang, YL, Cao, C, Stivers, JT, Song, F and Ichikawa, Y (2004) The merits of bipartite transition-state mimics for inhibition of uracil DNA glycosylase. Bioorg. Chem. 32:244-62
Abstract	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.
Links	PubMed Online version:10.1016/j.bioorg.2004.03.001
Keywords	Amides; Binding, Competitive; DNA Glycosylases/antagonists & inhibitors; DNA Repair; Enzyme Inhibitors/chemical synthesis; Escherichia coli Proteins/antagonists & inhibitors; Hydrogen-Ion Concentration; Molecular Mimicry; Oligonucleotides/chemical synthesis; Oligonucleotides/pharmacology; Phosphoric Acids; Structure-Activity Relationship; Uracil-DNA Glycosidase; Uridine/analogs & derivatives
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