MECHANISM AND MODELS OF DNA PHOTOLYASE

DNA光解酶的机制和模型

• 批准号: 2448884
• 负责人: OLAF G WIEST
• 金额: $ 10.3万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2448884
• 关键词: DNA repair; chemical synthesis; electron transport; enzyme activity; lyase; photobiology; photosensitizing agents; quantum chemistry

DESCRIPTION: Ultraviolet radiation of DNA causes cell death or skin cancer through formation of cyclobutane pyrimidine dimers (CPD) in the DNA. Many organisms protect their DNA by a light-induced repair mechanism, mediated by DNA photolyase. This extraordinary enzyme restores the genetic information by an electron transfer catalyzed (2+2) cycloreversion of the CPD. Knowledge of the reaction pathways is essential for an understanding of this cancer protection mechanism which is present in many organisms, but probably not in humans. The long term objective of the project is to understand electron transfer catalyzed DNA repair reactions and develop DNA photolyase mimics. Specific aims include: (i) understand the mechanism of cycloreversion at a molecular level; (ii) obtain the electronic and geometric structures of the molecules and transition states involved; (iii) determine the interactions by which DNA photolyase catalyzes the reaction and (iv) design and synthesize efficient, artificial catalysts with DNA photolyase activity. To reach these goals, the electron transfer catalyzed cycloreversion of the cis,syn and the trans,syn cyclobutane uracil dimer as well as some simple model systems will be investigated. The mechanistic questions will be addressed by a combination of experimental and theoretical methods. The kinetic isotope effects will be determined using a recently developed methodology. The results will be quantitatively interpreted by quantum mechanical calculations, particularly hybrid density functional methods. Interactions of the radical ions with the solvent and enzyme active site will be calculated by cavity and supermolecule approaches. The information obtained will be applied to the design of molecules that selectively bind either cis,syn or the trans,syn CPD by multiple hydrogen bonding and that are covalently attached to photosensitizers. The quantum yields for CPD repair will be optimized by using charged photosensitzers. These studies will increase our knowledge of DNA repair mechanisms and could ultimately lead to drugs to be used for skin cancer prevention.

描述：DNA的紫外线辐射会导致细胞死亡或皮肤癌 通过在DNA中形成环丁烷嘧啶二聚体（CPD）。 许多 通过光引起的修复机制保护其DNA，由 DNA光溶解酶。 这种非凡的酶恢复了遗传信息 通过电子转移催化（2+2）CPD的环旋转。 对反应途径的了解对于理解这一点至关重要 许多生物存在的癌症保护机制，但可能 不在人类中。 该项目的长期目标是了解 电子转移催化的DNA修复反应并发展DNA光解酶 模仿。 具体目的包括：（i）了解 在分子水平上的环鸟体； （ii）获得电子和 分子和过渡状态的几何结构； （iii） 确定DNA光溶解酶催化反应的相互作用 （iv）设计和合成具有DNA的有效的人造催化剂 光溶酶活性。 为了实现这些目标，电子传输催化 顺式，SYN和反式，Syn Cyclobutane Uracil二聚体的环鸟疗 以及一些简单的模型系统将被研究。 机械 实验和理论的结合将解决问题 方法。 动力学同位素效应将使用最近确定 开发的方法。 结果将通过定量解释 量子机械计算，尤其是混合密度功能 方法。 自由基与溶剂和酶的相互作用 主动部位将通过空腔和超分子方法计算。 这 获得的信息将应用于分子的设计 通过多种氢有选择地结合顺式，SYN或反式，SYN CPD 键合，并共价连接到光敏剂上。 量子 CPD维修的收率将通过使用带电的光敏仪优化。 这些研究将增加我们对DNA修复机制的了解，并且可以 最终导致药物用于预防皮肤癌。