MECHANISM AND MODELS OF DNA PHOTOLYASE

DNA光解酶的机制和模型

• 批准号: 6475951
• 负责人: OLAF G WIEST
• 金额: $ 10.52万
• 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 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6475951
• 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.

说明：DNA的紫外线辐射会导致细胞死亡或皮肤癌

项目成果

Toward an artificial oxidative DNA photolyase.

人工氧化 DNA 光裂合酶。

• DOI: 10.1021/jo0354600
• 发表时间: 2004
• 期刊: The Journal of organic chemistry.
• 作者: Pauvert,Mickael;Laine,Patrick;Jonas,Marco;Wiest,Olaf
• 通讯作者: Wiest,Olaf

Design, synthesis, and evaluation of a biomimetic artificial photolyase model.

• DOI: 10.1021/jo0494329
• 发表时间: 2004-11
• 期刊: The Journal of organic chemistry
• 作者: O. Wiest;Christopher B. Harrison;N. Saettel;R. Cibulka;M. Sax;B. König

Structure and reactivity of radical ions: new twists on old concepts.

• DOI: 10.1002/chem.200600554
• 发表时间: 2006-09-18
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Donoghue, Patrick J;Wiest, Olaf
• 通讯作者: Wiest, Olaf