MECHANISM AND MODELS OF DNA PHOTOLYASE

DNA光解酶的机制和模型

• 批准号: 6328971
• 负责人: OLAF G WIEST
• 金额: $ 10.11万
• 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/6328971
• 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：紫外线辐射的DNA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 生物体通过光诱导的修复机制来保护它们的DNA， DNA光解酶。 这种特殊的酶能恢复基因信息 通过CPD的电子转移催化的（2+2）环化逆转。 反应途径的知识对于理解这一点至关重要 癌症保护机制，存在于许多生物体中，但可能 而不是人类。 该项目的长期目标是了解 电子转移催化的DNA修复反应和开发DNA光裂合酶 模仿者 具体目标包括：（一）了解 在分子水平上的环化逆转;（ii）获得电子和 所涉及的分子和过渡态的几何结构;（iii） 确定DNA光解酶催化反应的相互作用 和（iv）设计和合成有效的人工催化剂与DNA 光解酶活性 为了达到这些目标，电子转移催化 顺式、顺式和反式、顺式环丁烷尿嘧啶二聚体的环逆转， 以及一些简单的模型系统将被研究。 机械论 问题将通过实验和理论相结合来解决 方法. 动力学同位素效应将使用最近的 发展方法论。 结果将通过以下方式进行定量解释： 量子力学计算，特别是混合密度泛函 方法. 自由基离子与溶剂和酶的相互作用 活性位的计算采用腔和超分子方法。 的 所获得的信息将应用于分子的设计， 通过多个氢选择性地结合顺式、顺式或反式、顺式CPD 键合并且共价连接到光敏剂。 量子 CPD修复的产率将通过使用带电光敏剂来优化。 这些研究将增加我们对DNA修复机制的了解， 最终导致用于预防皮肤癌的药物。