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 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.
Jiang
Yu Lin
YL
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205-2185, USA.
Cao
Chunyang
C
Stivers
James T
JT
Song
Fenhong
F
Ichikawa
Yoshi
Y
D000577:Amides; D001667:Binding, Competitive; D045647:DNA Glycosylases / Q000037:antagonists & inhibitors*; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors; D006863:Hydrogen-Ion Concentration; D018716:Molecular Mimicry; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000494:pharmacology; D010756:Phosphoric Acids; D013329:Structure-Activity Relationship; D051981:Uracil-DNA Glycosidase; D014529:Uridine / Q000031:analogs & derivatives*
D000577:Amides; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D009841:Oligonucleotides; D010756:Phosphoric Acids; C011067:phosphoramidic acid; D045647:DNA Glycosylases; D051981:Uracil-DNA Glycosidase; D014529:Uridine