A computational study of the structures and base-pairing properties of pyrrolizidine alkaloid-derived DNA adducts

IF 1.1 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
McKenzie Franz, Melanie Kebel, Pardeepak Sandhu, Denisa Moldovan, Taylor Adamitz, Rajwinder Kaur, Ye Eun Rebecca Jeong, S. Wetmore
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引用次数: 0

Abstract

Pyrrolizidine alkaloids (PAs) are found in many plants worldwide, including some in Canada. PAs have been linked to losses in livestock populations and development of human PA-diseases. Four PA-derived dehydrosupinidine (DHP) adducts formed at the exocyclic amino groups of DNA purines have been found in tumor tissue and flagged as potential biomarkers for tumor formation (denoted DHP-G/A–3 and DHP-G/A–4). Four additional adducts (DHP-G/A–1 and DHP-G/A–2) have also been identified, which differ in the stereochemistry at the DHP–nucleobase linker or DHP ring carbon containing the hydroxy group, as well as the length of the DHP–nucleobase linker. Since the impact of these distinct chemical features on adduct mutagenicity is currently unclear, the present work uses density functional theory calculations to uncover the structures and base-pairing properties of these experimentally-observed DHP-derived purine adducts. Adduct Watson-Crick base pairs involving the canonical partner are energetically and structurally feasible. However, the G/A–3 and G/A–4 adducts are also highly susceptible to mispairing with G. Indeed, the longer and more flexible DHP–nucleobase linker in these adducts affords interactions between the DHP moiety and the pairing G that are not possible for the G/A–1 and G/A–2 counterparts. Our data thus rationalize the experimental identification of this subset of adducts in liver tumor tissue, and provide key insights to guide future experimental and computational studies that investigate the replication and broader biological outcomes of DHP-derived lesions.
吡咯里西啶生物碱衍生 DNA 加合物结构和碱基配对特性的计算研究
吡咯里西啶生物碱(PAs)存在于世界各地的许多植物中,包括加拿大的一些植物。PAs 与牲畜数量减少和人类 PA 疾病的发生有关。在肿瘤组织中发现了在 DNA 嘌呤外环氨基上形成的四种 PA 衍生的脱水苏必啶(DHP)加合物,并被标记为肿瘤形成的潜在生物标志物(标记为 DHP-G/A-3 和 DHP-G/A-4)。此外,还发现了另外四种加合物(DHP-G/A-1 和 DHP-G/A-2),它们在 DHP-核碱基连接体或含有羟基的 DHP 环碳的立体化学结构以及 DHP-核碱基连接体的长度方面存在差异。由于这些不同的化学特征对加合物诱变性的影响目前尚不清楚,本研究利用密度泛函理论计算揭示了这些实验观察到的 DHP 衍生嘌呤加合物的结构和碱基配对特性。涉及典型伙伴的加合物 Watson-Crick 碱基配对在能量和结构上都是可行的。然而,G/A-3 和 G/A-4 加合物也非常容易与 G 配对错误。事实上,这些加合物中更长、更灵活的 DHP 核碱基连接体使 DHP 分子与配对的 G 之间产生了相互作用,而 G/A-1 和 G/A-2 加合物则不可能产生这种相互作用。因此,我们的数据合理地解释了肝脏肿瘤组织中这一亚群加合物的实验鉴定,并为指导未来研究 DHP 衍生病变的复制和更广泛的生物学结果的实验和计算研究提供了重要见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Canadian Journal of Chemistry
Canadian Journal of Chemistry 化学-化学综合
CiteScore
1.90
自引率
9.10%
发文量
99
审稿时长
1 months
期刊介绍: Published since 1929, the Canadian Journal of Chemistry reports current research findings in all branches of chemistry. It includes the traditional areas of analytical, inorganic, organic, and physical-theoretical chemistry and newer interdisciplinary areas such as materials science, spectroscopy, chemical physics, and biological, medicinal and environmental chemistry. Articles describing original research are welcomed.
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