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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Further insights into the mechanism of the reaction of activated bleomycin with DNA
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Further insights into the mechanism of the reaction of activated bleomycin with DNA

机译：关于活化博来霉素与DNA反应机理的进一步见解

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摘要

Bleomycin (BLM) is a glycopeptide anticancer drug that effectively carries out single- and double-stranded DNA cleavage. Activated BLM (ABLM), a low-spin ferric-hydroperoxide, BLM-Fe~(III) - OOH, is the last intermediate detected before DNA cleavage. We have previously shown through experiments and DFT calculations that both ABLM decay and reaction with H atom donors proceed via direct H atom abstraction. However, the rate of ABLM decay had been previously found, based on indirect methods, to be independent of the presence of DNA. In this study, we use a circular dichroism (CD) feature unique to ABLM to directly monitor the kinetics of ABLM reaction with a DNA oligonucleotide. Our results show that the ABLM + DNA reaction is appreciably faster, has a different kinetic isotope effect, and has a lower Arrhenius activation energy than does ABLM decay. In the ABLM reaction with DNA, the small normal k_H/k_D ratio is attributed to a secondary solvent effect through DFT vibrational analysis of reac-tant and transition state (TS) frequencies, and the lower E_a is attributed to the weaker bond involved in the abstraction reaction (C-H for DNA and N-H for the decay in the absence of DNA). The DNA dependence of the ABLM reaction indicates that DNA is involved in the TS for ABLM decay and thus reacts directly with BLM-Fe~(III)-OOH instead of its decay product.
机译：博来霉素（BLM）是一种糖肽抗癌药，可以有效地进行单链和双链DNA切割。活化的BLM（ABLM）是一种低旋转的氢过氧化铁BLM-Fe〜（III）-OOH，是DNA切割前检测到的最后一种中间体。先前我们通过实验和DFT计算表明，ABLM衰变和与H原子供体的反应都是通过直接H原子抽象进行的。但是，以前已经基于间接方法发现了ABLM衰减的速率与DNA的存在无关。在这项研究中，我们使用ABLM特有的圆二色性（CD）功能直接监视DNA寡核苷酸与ABLM反应的动力学。我们的结果表明，与ABLM衰变相比，ABLM + DNA反应明显更快，具有不同的动力学同位素效应，并且具有较低的Arrhenius活化能。在ABLM与DNA的反应中，正常的k_H / k_D比率小是由于通过对反应物和过渡态（TS）频率进行DFT振动分析而产生的次级溶剂效应，而较低的E_a则归因于与抽象反应（CH用于DNA，NH用于在没有DNA的情况下进行衰变）。 ABLM反应的DNA依赖性表明DNA参与TS中的ABLM衰变，因此直接与BLM-Fe〜（III）-OOH反应而不是其衰变产物。

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