X-ray Analyses of Polycyclic Hydrocarbon Metabolite Structures
X-ray Analyses of Polycyclic Hydrocarbon Metabolite Structures
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多环烃代谢物结构的 X 射线分析
DOI：
10.1021/bk-1985-0283.ch007
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发表时间：
1985
期刊：
影响因子：
--
通讯作者：
J. Glusker
中科院分区：
文献类型：
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作者：
J. Glusker
晶体结构的x射线衍射分析方法可用于研究致癌性多环芳烃（PAHs）及其活化代谢物的空间效应。例如，在多环芳烃的湾区附近存在甲基，大大增强了其致癌性；x射线研究显示了由甲基化引起的海湾区域平面内和面外的空间扭曲程度。在大多数多环芳烃中，分子的构象是由非键H····H相互作用决定的。如果分子是平面的，氢原子会靠得太近，那么键角和扭转角就会发生变化，以适应这种应变。此外，在更饱和的环体系中，如多环芳烃代谢物，氢原子之间的这种非键相互作用可能迫使羟基或其他取代基具有轴向构象而不是赤道构象。对二醇和环氧二醇等代谢物进行了分析。多环芳烃的致癌机制被认为涉及一种关键的信息大分子的烷基化，但目前尚不清楚。这种与蛋白质的相互作用已经通过多肽的烷基化来模拟；这表明烷基化发生了构象变化。目前还不可能研究被活化致癌物烷基化的DNA结构；这是因为DNA是一种纤维，它的结构顺序不足以确定晶体结构。然而，描述了一些核酸烷基化部分的晶体结构，特别是一些由DMBA的氯甲基衍生物烷基化的核苷。在这些烷基化产物的晶体中，加合物的多环芳烃部分倾向于位于晶体结构中其他核苷分子的碱基之间，尽管多环芳烃更弯曲的部分不参与这种堆叠。核糖的氧和部分多环芳烃（12-甲基苯[a]-蒽基衍生物中的甲基）之间似乎也存在相互作用。计算机模拟实验的一些初步研究表明，目前加合物的x射线数据与目前共价附着后相互作用的两种模型一致——多环芳烃部分在DNA碱基之间部分插层或芳烃基团位于DNA凹槽中的情况。
The methods of X-ray diffraction analysis of crystal structures can be used to investigate steric effects in carcinogenic polycyclic aromatic hydrocarbons (PAHs) and their activated metabolites. For example, the presence of a methyl group adjacent to the bay region of a PAH greatly enhances its carcinogenicity; X-ray studies have shown the extent of the steric distortions of the bay region, in-plane and out-of-plane, caused by this methylation. In most PAHs the conformation of the molecule is determined by nonbonded H····H interactions. If hydrogen atoms would approach each too closely if the molecule were planar, then bond angle and torsion angle changes are made to accommodate this strain. In addition, in more saturated ring systems such as PAH metabolites, this type of nonbonded interaction between hydrogen atoms may force a hydroxyl or other substituent to have an axial rather than an equatorial conformation. This has been analyzed for metabolites such as diols and diol epoxides.The mechanism of carcinogenesis by PAHs is believed to involve alkylation of an informational macromolecule in a critical, but at present unknown, manner. Such an interaction with a protein has been modelled by alkylation of a peptide; this showed a conformational change occurred on alkylation. It has not yet been possible to study the structure of DNA alkylated by an activated carcinogen; this is because DNA is a fiber and the structural order in it is not sufficient for a crystal structure determination. However the crystal structures of some alkylated portions of nucleic acids are described, particularly some nucleosides alkylated by chloromethyl derivatives of DMBA. In crystals of these alkylation products the PAH portion of the adduct shows a tendency to lie between the bases of other nucleoside molecules in the crystal structure, although the more buckled part of the PAH does not take part in this stacking. There also appears to be an interaction between the oxygen of the ribose sugar and part of the PAH (the methyl group in a 12-methylbenz[a]-anthracenyl derivative). Some preliminary studies in computer modelling experiments show that, at present, the X-ray data on adducts are consistent with both current models of interaction after covalent attachment - partial intercalation of the aromatic portion of the PAH between the bases of DNA or the situation where the aromatic group lies in a groove of DNA.