Collaborative Research: A systems approach toward understanding the diversification of tropane and granatane alkaloid biosynthesis

合作研究：了解托烷和谷烷生物碱生物合成多样化的系统方法

• 批准号: 1714093
• 负责人: Cornelius Barry
• 金额: $ 34.41万
• 依托单位: Michigan State 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 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1714093&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.

该项目的目的是使用比较方法来研究三个不同植物家族中两个有机氮的合成途径，以发现新基因并检验这两种途径在每个家族中彼此独立发展的假设。这些生物碱捍卫植物免受昆虫，其他害虫和病原体的影响，并被人类用作调味料，香料，农药和药物。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个机会。 此外，通过在合作伙伴实验室之间实施交流，以促进跨学科技能的发展，可以增强研究生培训。正式的本科交流将通过招募来自德克萨斯理工大学或爱荷华州立大学的女性和代表性不足的少数族裔学生来完成密歇根州立大学的本科生研究经验。 该项目还将直接与爱荷华州的当地社区学院合作，为社区大学的学生接触结构生物学。型和格拉纳烷生物碱含有核心双环环结构，并散布在无关的植物家庭中。 该研究项目将利用转录组学和代谢组学的自上而下方法，以及基于比较的功能，生化和结构生物学方法，以阐明途径和机制，这些途径和机制是基于药物上重要的tropane和gropane和Granatane Alkaloids的生物合成的基础。基因发现将发生在三个独特而重要的农作物家族中：铜菜科，lythraceae和erilythroxylaceae，并且将结果的数据与甲酸盐酸科中既定的托型途径进行了比较。这种比较方法将用于检验以下假设：在植物谱系中，植物生物碱系统独立出现的型不同物种的型物种生物合成途径中的新型生物催化活性。此外，该研究还探讨了托帕尼生物碱代谢的不同组成部分独立选择以建立新的代谢系统（例如Granatane生物碱）。总体而言，这种方法将导致人们对基质和花纹烷生物碱生物合成的了解增强。此外，对导致Tropane和Granatane生物碱的生物合成步骤的了解对于这些药理活性化学物质的定量建模和代谢工程至关重要。

项目成果

An Automated Data-Driven Pipeline for Improving Heterologous Enzyme Expression

用于改善异源酶表达的自动化数据驱动管道

• DOI: 10.1021/acssynbio.8b00486
• 发表时间: 2019
• 期刊: ACS Synthetic Biology
• 影响因子: 4.7
• 作者: Wrenbeck, Emily E.;Bedewitz, Matthew A.;Klesmith, Justin R.;Noshin, Syeda;Barry, Cornelius S.;Whitehead, Timothy A.
• 通讯作者: Whitehead, Timothy A.

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.