THEORETICAL MODELS FOR CYTOCHROME P-450 MEDIATED HYDROGEN ATOM ABSTRACTION

细胞色素 P-450 介导的氢原子抽象的理论模型

• 批准号: 3878919
• 负责人: K KORZEKWA
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3878919
• 关键词: chemical binding; chemical group; chemical models; chemical reaction; cytochrome P450; drug metabolism; enzyme mechanism; enzyme model; enzyme substrate; hydrogen; isozymes; oxidation reduction reaction; oxygenases; quantum chemistry; toxicant interaction

The ubiquitous superfamily of enzymes, the cytochrome P-450s, continue to be the focus of many diverse research efforts. Interest in these heme containing monooxygenases stem from their ability to catalyze the oxidation of a wide variety of lipophilic endogenous (i.e. steroids, prostaglandins and fatty acids) and exogenous (drugs and environmental contaminants) compounds. Because of their importance in drug metabolism and toxicity, predictive models for cytochrome P450 oxidations could be extremely useful. We have used molecular modeling techniques to develop a predictive model for cytochrome P-450 hydrogen abstraction reactions. Of several model oxygen radicals studied, the p-nitrosophenoxy radical has the most appropriate transition state symmetry for use as a model for P-450 mediated hydrogen atom abstractions. Using this model, a linear correlation was observed between H and a combination of H(R) and either the modified Swain-Lupton resonance parameter or the ionization potential of the radical formed. The latter relationship gave an estimated standard deviation of the predicted H of 0.8 kcal/mol. This suggests that it may be possible to obtain an estimate of the relative ability for any carbon-hydrogen bond to undergo P-450 mediated hydrogen atom abstraction by calculating the relative stability and ionization potential of the resulting radical. In addition reactants and products for 54 hydroxylation and desaturation reactions were modeled and used to predict the relative tendency for each reaction to occur.

无处不在的酶超家族，细胞色素P-450，继续 成为许多不同研究工作的焦点。对这些血红素的兴趣 含有单加氧酶的植物来源于它们催化氧化的能力 多种亲脂性内源性（即类固醇、肾上腺素） 和脂肪酸）和外源性（药物和环境污染物） 化合物.由于它们在药物代谢和毒性中的重要性， 细胞色素P450氧化的预测模型可能非常有用。 我们已经使用分子建模技术开发了一个预测模型 用于细胞色素P-450夺氢反应。几种型号 氧自由基的研究，p-亚硝基苯氧基自由基具有最多的 适当的过渡态对称性用作P-450介导的模型 氢原子抽象使用该模型，线性相关性为 在H和H（R）和修饰的 自由基的Swain-Lupton共振参数或电离势 形成了后一种关系给出了 预测H为0.8 kcal/mol。这表明， 获得任何碳-氢键的相对能力的估计， 通过计算P-450介导的氢原子提取， 所产生的自由基的相对稳定性和电离电位。在 用于54羟基化和去饱和的加成反应物和产物 反应进行了建模，并用于预测每种反应的相对趋势。 反应发生。