From genes to molecules: mining bacterial genomes for new enzyme reactions

从基因到分子：挖掘细菌基因组以寻找新的酶反应

• 批准号: 298316-2011
• 负责人: Zechel, David
• 金额: $ 2.19万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=548294
• 关键词: genes; molecules; mining; bacterial; genomes

Is it possible that a handful of soil or a pail of seawater could hold the solution to some of the pressing environmental and human health issues facing the world today? The advent of large scale DNA sequencing has revealed a molecular world that may indeed provide the answer to cleaning up pollutants or the path to the next wonder drug. Inspired by this new era of DNA driven discovery of new chemical reactions and molecules, we propose to explore enzymes that have the potential to improve environmental and human health. Specifically, we will study the remarkable carbon-phosphorus bond cleaving reaction of carbon-phosphorus lyase. We will also study the PhnY / PhnZ organophosphonate degradation system, recently identified through screening of marine DNA, which appears to cleave carbon-phosphorus bonds through a new reaction mechanism. Both enzyme systems have the potential to degrade environmental pollutants known as organophosphonates, a component of herbicides, insecticides, chemical warfare agents, and surfactants. We will also study enzymes that are involved in the biosynthesis of 'halogenated' natural products, a large family of bioactive molecules that have great potential to provide new anticancer and antibiotic drugs. Specifically we examine the unique reaction catalyzed by the 'halogenase' involved in the biosynthesis of one of the first wonder drugs of the 20th century, the antibiotic chloramphenicol. Using information gained from genome sequencing, we will also characterize the biosynthesis of, nucleocidin, a rare example of a fluorine substituted natural product. Identification of the enzyme that incorporates the fluorine atom, a 'fluorinase', could lead to a biocatalyst for the synthesis of fluorine containing nucleosides, which are of great interest as antiviral inhibitors. Overall our proposal contains 4 areas of study that will train 4 graduate students, as well as a yearly summer student, in a variety of skills, from molecular biology and microbiology to synthetic chemistry. These skills are in high demand in the increasingly multidisciplinary environment that exists in pharmaceutical and biotechnology companies.

一把土壤或一桶海水是否有可能解决当今世界面临的一些紧迫的环境和人类健康问题？大规模 DNA 测序的出现揭示了一个分子世界，它确实可能提供清理污染物的答案或找到下一种神奇药物的途径。受 DNA 驱动新化学反应和分子发现的新时代的启发，我们建议探索具有改善环境和人类健康潜力的酶。具体来说，我们将研究碳磷裂解酶显着的碳磷键断裂反应。我们还将研究最近通过海洋 DNA 筛选发现的 PhnY / PhnZ 有机膦酸酯降解系统，该系统似乎可以通过新的反应机制裂解碳磷键。这两种酶系统都有可能降解被称为有机膦酸盐的环境污染物，有机膦酸盐是除草剂、杀虫剂、化学战剂和表面活性剂的成分。我们还将研究参与“卤化”天然产物生物合成的酶，这是一大类生物活性分子，具有提供新抗癌和抗生素药物的巨大潜力。具体来说，我们检查了“卤化酶”催化的独特反应，该反应涉及 20 世纪第一个神奇药物之一——抗生素氯霉素的生物合成。利用从基因组测序中获得的信息，我们还将表征杀核素的生物合成，这是氟取代天然产物的罕见例子。鉴定出含有氟原子的酶（一种“氟酶”）可能会产生一种用于合成含氟核苷的生物催化剂，这种核苷作为抗病毒抑制剂非常受关注。总体而言，我们的提案包含 4 个研究领域，将培训 4 名研究生以及一名每年暑期学生，学习从分子生物学、微生物学到合成化学等各种技能。在制药和生物技术公司日益多学科的环境中，对这些技能的需求量很大。