期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 21, 期 17, 页码 4969-4972出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.05.085
关键词
Base excision repair; DNA glycosylase; Pyrrolidine analogs; Transition state analogs; 8-Oxo-7,8-dihydro-2-deoxyguanosine; hOGG1; Fpg; Nei; hNEIL1
资金
- National Cancer Institute of the National Institutes of Health [CA67985, CA090689]
- NSF [0840444]
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.
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