Deligkaris Christos, Millam Evan
Department of Geology and Physics , University of Southern Indiana , Evansville , IN 47712 , USA . Email:
Department of Chemistry , University of Southern Indiana , Evansville , IN 47712 , USA.
Toxicol Res (Camb). 2019 Apr 17;8(4):531-543. doi: 10.1039/c9tx00010k. eCollection 2019 Jul 1.
The tobacco smoke -nitrosamine, NNK, is an important carcinogen. It has been shown to induce lung, liver, and pancreatic cancer in animals. Its metabolites are associated with lung cancer in tobacco smokers. Our work focuses upon the physical interaction of NNK diazonium ion with DNA. This species is implicated in the formation of pyridyloxobutyl adducts, reacting with DNA bases and phosphate groups. Past research has investigated the metabolic activation of NNK by various enzymes, subsequent adduct formation with DNA, and the role of these adducts in mutagenesis. We present the first study of the physical interaction of NNK diazonium ion with TP53 (exon 5), a frequently mutated human tumor suppressor gene. We identify physical binding sites found free energy minimization in computational docking simulations. These structures represent local potential energy minima in this system and suggest plausible sites for adduct formation.
烟草烟雾中的亚硝胺NNK是一种重要的致癌物。已证明它可在动物体内诱发肺癌、肝癌和胰腺癌。其代谢产物与吸烟人群的肺癌有关。我们的工作重点是NNK重氮离子与DNA的物理相互作用。该物质与吡啶氧基丁基加合物的形成有关，可与DNA碱基和磷酸基团发生反应。过去的研究调查了NNK被各种酶的代谢激活、随后与DNA形成加合物以及这些加合物在诱变中的作用。我们首次对NNK重氮离子与TP53（第5外显子）进行了物理相互作用的研究，TP53是一种经常发生突变的人类肿瘤抑制基因。我们在计算对接模拟中通过自由能最小化确定了物理结合位点。这些结构代表了该系统中的局部势能最低点，并暗示了加合物形成的可能位点。
