Novel Catalases and their Products

新型过氧化氢酶及其产品

• 批准号: 7100044
• 负责人: ALAN R. BRASH
• 金额: $ 29.02万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7100044
• 关键词: Fusarium; X ray crystallography; aerobiosis; analog; bacterial proteins; catalase; chemical synthesis; chimeric proteins; cyclization; cyclopentane; enzyme activity; fungal proteins; heme; ligands; pathologic process; protein binding; protein structure function

DESCRIPTION (provided by applicant): The long-term objective of this application is to elucidate the roles of a novel group of proteins related in sequence and structure to catalase and to define the biochemistry and chemistry of their reactions and novel products. Catalase is renowned for its key role in the oxidative defense of all aerobic organisms. One can anticipate selective reactions of these new catalase relatives with potential oxidative metabolism and/or functioning in the disposition of natural peroxides. The prototypical enzyme of this proposal is an allene oxide synthase, an enzyme that catalyzes a cytochrome P450-type of reaction yet which exhibits distinct sequence homology to catalase. In Aim 1, a newly available X-ray crystal structure of the catalase-related AOS will be used to reveal the mechanistic basis of catalysis and the comparisons and contrasts with human catalase. The goal is to provide an understanding of the ability to catalyze P450-type chemistry within the catalase fold. Aim 2 will focus on analysis of the catalytic activities of other novel enzyme candidates that have similar sequence characteristics defined as retention of the heme-binding features of a catalase within an unusually short polypeptide for catalases of only ~40kD. These enzymes occur in organisms that include bacteria of importance for their pathogenicity and a crop blight fungus characterized as a major threat to the world's food supply. Allene oxides are of major importance in biotechnology and their cyclopentenone derivatives are also studied for their potent antineoplastic effects. Aim 3 will seek to establish the structure and precise stereochemistry of natural allene oxides and especially structural issues pertinent to their cyclizations. This is of fundamental interest in understanding the nature of allene oxide synthase reactions as well as the chemistry of cyclopentenone synthesis. The results of this study will provide new insights and a new way of thinking about the enzymatic capabilities of a long-recognized protein family with established roles as a sentinel at the forefront of oxidative defense.

描述（由申请人提供）：本申请的长期目标是阐明与过氧化氢酶的序列和结构相关的新型蛋白质的作用，并定义其反应和新产品的生物化学和化学。过氧化氢酶以其在所有有氧生物的氧化防御中的关键作用而闻名。人们可以预期这些新的过氧化氢酶亲戚具有潜在的氧化代谢和/或在天然过氧化物的处置中的作用。该提案的原型酶是一种艾烯氧化物合酶，一种酶，催化反应的细胞色素P450型，但与过酶表现出不同的序列同源性。在AIM 1中，将使用与过氧化氢酶相关的AOS的新近可用的X射线晶体结构来揭示催化的机械基础以及与人过氧化氢酶的比较和对比。目的是提供了解在过氧化氢酶折叠中催化P450型化学反应的能力。 AIM 2将集中于对其他新型酶的催化活性的分析，这些新酶的序列特征的定义为相似的序列特征，该序列特征的保留量仅在〜40KD的过氧化氢酶的异常短多肽中保留了血红素结合特征。这些酶发生在包括对其致病性重要性的细菌和农作物枯萎的真菌，其特征是对世界粮食供应的主要威胁。在生物技术中，艾琳（Allene）氧化物至关重要，还研究了其环烯酮衍生物的有效抗塑性作用。 AIM 3将寻求建立自然氧化物的结构和精确的立体化学，尤其是与其环化有关的结构问题。这是理解艾琳氧化物合酶反应的性质以及环戊酮合成的化学性质的基本兴趣。这项研究的结果将提供新的见解和一种新的思考方式，以了解长期认可的蛋白质家族的酶促能力，该家族在氧化防御的最前哨中既定角色。