Collaborative Research: A Systems Approach Toward Understanding the Diversification of Tropane and Granatane Alkaloid Biosynthesis

合作研究：了解托烷和石榴烷生物碱生物合成多样化的系统方法

• 批准号: 1714236
• 负责人: Michael Latham
• 金额: $ 33.23万
• 依托单位: Texas Tech University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1714236&HistoricalAwards=false
• 关键词: Collaborative; Research; Systems; Approach; Toward

The goal of this project is to use comparative approaches to investigate the synthesis pathways of two organic, nitrogen containing compounds in three different plant families to discover new genes and test the hypothesis that these two pathways developed independently of one another in each family. These alkaloids defend plants against insects and other pests and pathogens, and are used by humans as flavourings, fragrances, pesticides and medicines. This research will provide multiple opportunities for interdisciplinary training in genomics, structural biology, biochemistry, and analytical chemistry to graduate and undergraduate students. Furthermore, graduate student training will be enhanced through implementation of exchanges between partner labs to facilitate the development of interdisciplinary skills. Formal undergraduate exchanges will be accomplished by the recruitment of female and underrepresented minority students from Texas Tech or Iowa State University into a Research Experience for Undergraduates (REU) Program at Michigan State University. The project also will work directly with a local Community College in Iowa to provide Community College students with exposure to structural biology.Tropane and granatane alkaloids contain a core bicyclic ring structure and appear scattered across unrelated plant families. The research project will utilize a top down approach of combined transcriptomics and metabolomics coupled with comparative functional, biochemical and structural biology based approaches to elucidate the pathways and mechanisms that underlie the biosynthesis of the pharmaceutically important tropane and granatane alkaloids. Gene discovery will occur in three distinct and important crop families: Brassicaceae, Lythraceae and Erythroxylaceae and the resulting data will be compared to an established tropane pathway in the Solanaceae. This comparative approach will be used to test the hypothesis that novel biocatalytic activities within the tropane biosynthetic pathways of distinct species are the source of the independent emergence of the tropane alkaloid system within the plant lineage. Additionally, the research explores the possibility that the different components of tropane alkaloid metabolism were independently co-opted to build new metabolic systems (e.g. granatane alkaloids). Overall, this approach will lead to enhanced understanding of tropane and granatane alkaloid biosynthesis. Moreover, knowledge of the biosynthetic steps leading to tropane and granatane alkaloids is crucial for quantitative modeling and metabolic engineering of these pharmacologically active chemicals.

该项目的目标是使用比较方法来研究三种不同植物家族中两种有机含氮化合物的合成途径，以发现新的基因并测试这两种途径在每个家族中独立发展的假设。这些生物碱保护植物免受昆虫和其他害虫和病原体的侵害，并被人类用作调味剂，香料，杀虫剂和药物。这项研究将为研究生和本科生提供基因组学，结构生物学，生物化学和分析化学的跨学科培训的多种机会。 此外，将通过实施伙伴实验室之间的交流来加强研究生培训，以促进跨学科技能的发展。正式的本科生交流将通过招募来自德克萨斯理工大学或爱荷华州州立大学的女性和代表性不足的少数民族学生进入密歇根州立大学的本科生研究经验（REU）项目来完成。 该项目还将直接与爱荷华州的一所当地社区学院合作，为社区学院的学生提供结构生物学方面的知识。托烷和石榴烷生物碱含有一个核心双环结构，分散在不相关的植物科中。 该研究项目将利用自上而下的方法，结合转录组学和代谢组学，并结合比较功能，生物化学和结构生物学方法，以阐明药学上重要的托烷和石榴烷生物碱生物合成的途径和机制。基因发现将发生在三个不同的和重要的作物家族：菊科，千屈菜科和Erythroxylaceae和所得到的数据将比较在茄科中建立的托烷途径。这种比较的方法将被用来测试的假设，即新的生物催化活性内的不同物种的莨菪烷生物合成途径的植物谱系内的莨菪烷生物碱系统的独立出现的来源。此外，该研究还探索了托烷生物碱代谢的不同组分独立地被选择以建立新的代谢系统（例如石榴烷生物碱）的可能性。总的来说，这种方法将导致加强对托烷和石榴烷生物碱生物合成的理解。此外，知识的生物合成步骤，导致托烷和石榴烷生物碱是至关重要的定量建模和代谢工程的这些活性化学品。

项目成果

Tropinone synthesis via an atypical polyketide synthase and P450-mediated cyclization

• DOI: 10.1038/s41467-018-07671-3
• 发表时间: 2018-12-11
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Bedewitz, Matthew A.;Jones, A. Daniel;Barry, Cornelius S.
• 通讯作者: Barry, Cornelius S.