Profiling base excision repair glycosylases with synthesized transition state analogs

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 17; pp. 4969 - 4972
• Main Authors: Chu, Aurea M., Fettinger, James C., David, Sheila S.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-09-2011; Elsevier
• Subjects: 8-Oxo-7,8-dihydro-2-deoxyguanosine; Base excision repair; Base Sequence; Biocatalysis; Biological and medical sciences; DNA glycosylase; DNA Glycosylases - metabolism; DNA Repair; Fpg; hNEIL1; hOGG1; Humans; Medical sciences; Miscellaneous; Nei; Pharmacology. Drug treatments; Pyrrolidine analogs; Pyrrolidines - pharmacology; Substrate Specificity; Transition state analogs; Nei; hOGG1; DNA glycosylase; Fpg; hNEIL1; Base excision repair; Pyrrolidine analogs; Transition state analogs; 8-Oxo-7,8-dihydro-2-deoxyguanosine; Aminoalcohol; Excision; Enzyme; Nitrogen heterocycle; Molecular interaction; Glycosylases; Biological fixation; Structure activity relation; Biomimetic compound; DNA; Transition state; Hydrolases; Affinity; Repair; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.05.085

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 (Kd∼pM) with DNA duplexes containing the 1NBn and 1N nucleotide. Notably, comparison of the Kd 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.