title: Profiling base excision repair glycosylases with synthesized transition state analogs.
abstract: Two base excision repair glycosylase (BER) transition state (TS) mimics, (3R,4R)-1-benzyl (hydroxymethyl) pyrrolidin-3-ol (1NBn) and (3R,4R)-(hydroxymethyl) pyrrolidin-3-ol (1N), were synthesized using an improved method. Several BER glycosylases that repair oxidized DNA bases, bacterial formamidopyrimdine glycosylase (Fpg), human OG glycosylase (hOGG1) and human Nei-like glycosylase 1 (hNEIL1) exhibit exceptionally high affinity (K(d)∼pM) with DNA duplexes containing the 1NBn and 1N nucleotide. Notably, comparison of the K(d) values of both TS mimics relative to an abasic analog (THF) in duplex contexts paired opposite C or A suggest that these DNA repair enzymes use distinctly different mechanisms for damaged base recognition and catalysis despite having overlapping substrate specificities.
authors.affiliation: Department of Chemistry, University of California, Davis, Building 143, One Shields Avenue, Davis, CA 95616, United States.
authors.forename: Aurea M
authors.initials: AM
authors.lastname: Chu
authors.forename: James C
authors.initials: JC
authors.lastname: Fettinger
authors.forename: Sheila S
authors.initials: SS
authors.lastname: David
mesh_terms: D001483:Base Sequence; D055162:Biocatalysis; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D006801:Humans; D011759:Pyrrolidines / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D011759:Pyrrolidines; D045647:DNA Glycosylases