Profiling base excision repair glycosylases with synthesized transition state analogs

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Chu, Aurea M.¹  Fettinger, James C.¹  David, Sheila S.¹ 

[1] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA

关键词: Base excision repair;    DNA glycosylase;    Pyrrolidine analogs;    Transition state analogs;    8-Oxo-7,8-dihydro-2-deoxyguanosine;    hOGG1;    Fpg;    Nei;    hNEIL1;   

DOI  :  10.1016/j.bmcl.2011.05.085

来源: Elsevier

【 摘 要 】

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 similar to 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. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

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