Trzupek John D, Gottesfeld Joel M, Boger Dale L
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nat Chem Biol. 2006 Feb;2(2):79-82. doi: 10.1038/nchembio761. Epub 2006 Jan 15.
(+)-Yatakemycin (1, Fig. 1) and (+)-duocarmycin SA (2) are exceptionally potent, naturally occurring antitumor agents that derive their biological properties through a characteristic sequence-selective DNA-alkylation reaction. Studies have shown that both the AT-rich binding selectivity (shape-selective recognition) and the alkylation catalysis (shape-dependent catalysis) that contribute to the alkylation selectivity are dependent on the DNA minor groove shape and size characteristics of an AT-rich sequence (ref. 6 and references therein; refs. 7,8). Here we report the alkylation properties of yatakemycin and duocarmycin SA on free DNA (alpha-satellite DNA) and the same sequence bound in a nucleosome core particle (NCP) modeling the state of DNA in eukaryotic cells. Both compounds showed a clear, relatively unaltered ability to alkylate DNA packaged in NCPs in terms of both alkylating efficiency and sequence selectivity, despite the steric and conformational perturbations imposed by NCP packaging. These findings highlight the dynamic nature of NCP-bound DNA and illustrate that cell- and protein-free DNA-alkylation studies of members of this class of antitumor drugs provide valuable insights into their properties.
（+）- yatakemycin（1，图1）和（+）- 多卡霉素SA（2）是极具活性的天然抗肿瘤剂，它们通过独特的序列选择性DNA烷基化反应获得生物学特性。研究表明，有助于烷基化选择性的富含AT的结合选择性（形状选择性识别）和烷基化催化（形状依赖性催化）均取决于富含AT序列的DNA小沟形状和大小特征（参考文献6及其中的参考文献；参考文献7,8）。在此，我们报告了yatakemycin和多卡霉素SA对游离DNA（α-卫星DNA）以及结合在核小体核心颗粒（NCP）中的相同序列（模拟真核细胞中的DNA状态）的烷基化特性。尽管NCP包装会带来空间和构象扰动，但就烷基化效率和序列选择性而言，这两种化合物对包装在NCP中的DNA进行烷基化的能力均表现出明显且相对未改变的特性。这些发现突出了与NCP结合的DNA的动态性质，并表明对这类抗肿瘤药物成员进行无细胞和无蛋白质的DNA烷基化研究为了解其特性提供了有价值的见解。
