酶催化甲苯降解和异常 DNA 光产物修复-猫眼课题宝

酶催化甲苯降解和异常 DNA 光产物修复

批准号：

8117523

负责人：

Lei Li

金额：

$24.9万

依托单位：

INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS

依托单位国家：

美国

项目类别：

财政年份：

2009

资助国家：

美国

项目状态：

已结题

起止时间：

2009-09-01 至 2013-07-31

来源：

https://reporter.nih.gov/project-details/8117523

关键词：

Active Sites Adopted Amino Acids Anthrax disease Bacillus anthracis Bacteria Bacterial Spores Biochemical Process Biological Process Botulism Carbon Catalysis Chemistry Clostridium botulinum Coenzymes Coupled Crystallography DNA DNA Repair DNA Repair Enzymes DNA Repair Pathway DNA biosynthesis DNA photoproducts DNA-Protein Interaction Disease Endospore-Forming Bacteria Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Excision Fermentation Food Poisoning Free Radicals Generations Germination Goals Human Hydrocarbons Isotopes Kinetics Measurable Mediating Methods Microbe Mutagenesis Names Nature Organic Chemistry Oxidation-Reduction Phase Proteins Reaction Reproduction spores Research Research Project Grants S-Adenosylmethionine Snoring Source Sterilization Structure Surveys Thymine Toluene analog base chemical kinetics crosslink enzyme mechanism in vivo inhibitor/antagonist medical schools novel pollutant prevent public health relevance repaired spore photoproduct lyase sugar tool ultraviolet damage ultraviolet irradiation

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Enzynnes utilize organic radicals to catalyze a variety of important nnetabolic reactions. The overall goal of this research is to delineate the mechanistic details of radical generation and control by these enzymes. This research in the ROO phase will focus on a DNA repair enzyme named spore photoproduct lyase (SPL). SPL utilizes S-adenosylmethionine (SAM) coupled by a unique [4Fe-4S] cluster to generate the reactive organic radicals to repair the unique T-T crosslink 5-thyminyl-5, 6-dihydrothymine (commonly called spore photoproduct, SP) formed upon UV irradiation. SPL exists in the spores of bacteria such as B. subtilis and B. anthracis. It adopts a "direct reverse" strategy to repair SP, meaning that the UV damage is quickly reversed with neither removal nor replacement of the damaged thymine bases. It thus represents a unique DNA repair pathway in Nature. In addition, the efficient DNA repair catalyzed by SPL makes UV irradiation no longer lethal to the spore-forming bacteria. To understand the SPL mediated DNA repair reaction, chemical, kinetic, spectroscopic, and mutagenic methods will be employed. The objectives include: investigating the SPL activity using substrates with a wide range of DNA secondary structures, probing the reaction mechanism by SP analogues (mechanism-based enzyme inhibitors), and examining the kinetic isotope effects and reaction reversibility. In addition, the redox potential of the [4Fe-4S] cluster will be determined and the influence of SAIV! and key amino acids to the redox potential will be investigated. Understanding the enzyme mechanism will help us identify potential SPL inhibitors. As SPL is the key enzyme to repair the UV damage in endospore-forming bacteria, inhibiting its activity in vivo will prevent the bacteria from fixing these damages at the germination phase. In combination with the SPL inhibitor, UV irradiation will regain its power as a cheap and convenient tool for sterilization purpose.

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