Department of Chemistry, University of California, Davis, Building 143, One Shields Avenue, Davis, CA 95616, United States.
Bioorg Med Chem Lett. 2011 Sep 1;21(17):4969-72. doi: 10.1016/j.bmcl.2011.05.085. Epub 2011 May 30.
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.
两种碱基切除修复糖苷酶（BER）过渡态（TS）模拟物，（3R，4R）-1-苄基（羟甲基）吡咯烷-3-醇（1NBn）和（3R，4R）-（羟甲基）吡咯烷-3-醇（1N），使用改进的方法合成。几种修复氧化 DNA 碱基的 BER 糖苷酶，如细菌的 formamidopyrimdine 糖苷酶（Fpg）、人 OG 糖苷酶（hOGG1）和人 Nei 样糖苷酶 1（hNEIL1），与含有 1NBn 和 1N 核苷酸的 DNA 双链体表现出极高的亲和力（Kd∼pM）。值得注意的是，将这两种 TS 模拟物的 Kd 值与在双链体背景下配对 C 或 A 的无碱基类似物（THF）进行比较表明，尽管这些 DNA 修复酶具有重叠的底物特异性，但它们使用截然不同的机制来识别和催化受损碱基。
