An integrated approach to camptothecin biosynthesis discovery and engineering

喜树碱生物合成发现和工程的综合方法

• 批准号: RGPIN-2019-05473
• 负责人: Dang, ThuThuy
• 金额: $ 2.7万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=686881
• 关键词: integrated; approach; camptothecin; biosynthesis; discovery

The Plant Bioactive Compounds Research (PlantBioCoRe) Laboratory aims to decode the genomic and biochemical features that contribute to the vast diversity of plants' specialized metabolism, and to translate this knowledge into innovative biotechnologies to meet the societal needs of high-value chemicals.***Plants produce upwards of 200,000 distinct specialized metabolites, many of which are invaluable nutrients, commodity products, and therapeutics. Their structural complexity signifies that their biosynthetic pathways are outstanding sources of new biocatalysts for synthetic biology applications. Unfortunately, research progress in plant specialized metabolism has lagged, in large part due to the complexities of plant systems. Camptothecin (anticancer), Taxol (anticancer), quinine (antimalarial) are just a few examples of the important plant metabolic pathways that remain uncharacterized, and approaches to exploit these rich metabolism resources have thus been unrealized.***PlantBioCoRe's immediate focus is on the anticancer compound campothecin, produced by the tree Camptotheca acuminata. We will integrate a suite of innovative and modern bioinformatic, analytical, biochemical, and molecular genetic approaches to unravel the unprecedented biochemistry harboured within the biosynthesis of camptothecin and related valuable phytochemicals. The short-term objectives are: (i) to discover new biosynthetic enzymes; (ii) to functionally and structurally characterize these biocatalysts; (iii) to generate alkaloid structural and functional diversities; and (iv) to reconstitute parts of the camptothecin biosynthetic pathway. Initial understanding of enzymatic steps in the biosynthesis will inform our long-term investigation on the temporal and spatial organization of these enzymes and metabolites, paving the way for successful engineering and reconstitution of not only camptothecin but also other alkaloid pathways in 5-10 years. A comprehensive understanding of camptothecin production will allow us to provide access to chemical transformations unique to plants, guide the discovery of new biosynthtic pathways, illuminate the evolution of existing pathways, and build an enabling enzymatic toolbox for metabolic engineering. ***In addition to a more expanded and detailed picture of alkaloid biosynthesis, our research program provides unique opportunities for highly-qualified personnel to develop advanced technical skills in bioinformatics, enzymology, biochemistry, project management and scientific communication. These experiences would allow them to be highly competitive in the research-oriented job market and contribute to the growth of Canada's knowledge-driven economy. Our research program will illuminate how Nature creates extensive structural diversity from a few simple starting materials, and offer sustainable alternatives to chemical extraction from plants or synthesis from petrochemicals, therefore, benefiting both Canadian academic and public sectors. *****

植物生物活性化合物研究（PlantBioCoRe）实验室旨在解码基因组和生物化学特征，这些特征有助于植物专业代谢的巨大多样性，并将这些知识转化为创新的生物技术，以满足社会对高价值化学品的需求。植物产生超过20万种不同的特殊代谢物，其中许多是无价的营养物质、商品和治疗药物。它们的结构复杂性意味着它们的生物合成途径是合成生物学应用的新型生物催化剂的杰出来源。不幸的是，由于植物系统的复杂性，植物特化代谢的研究进展滞后。喜树碱（抗癌）、紫杉醇（抗癌）、奎宁（抗疟疾）只是未被描述的重要植物代谢途径的几个例子，因此开发这些丰富代谢资源的方法尚未实现。***PlantBioCoRe目前的重点是由喜树（Camptotheca acuminata）产生的抗癌化合物campothecin。我们将整合一套创新的现代生物信息学、分析学、生化学和分子遗传学方法，揭示喜树碱和相关有价值的植物化学物质的生物合成中前所未有的生物化学。短期目标是：(i)发现新的生物合成酶；（ii）对这些生物催化剂进行功能和结构表征；（iii）产生生物碱结构和功能的多样性；（iv）重建喜树碱生物合成途径的部分。初步了解生物合成过程中的酶促步骤将为我们对这些酶和代谢物的时空组织的长期研究提供信息，为在5-10年内成功地设计和重建喜树碱以及其他生物碱途径铺平道路。对喜树碱生产的全面了解将使我们能够获得植物特有的化学转化，指导新的生物合成途径的发现，阐明现有途径的进化，并为代谢工程建立一个使能的酶工具箱。***除了对生物碱生物合成有更广泛和详细的了解外，我们的研究项目还为高素质人才提供了在生物信息学、酶学、生物化学、项目管理和科学交流方面发展先进技术技能的独特机会。这些经验将使他们在研究型就业市场上具有很强的竞争力，并为加拿大知识驱动型经济的发展做出贡献。我们的研究项目将阐明大自然如何从几种简单的起始材料中创造出广泛的结构多样性，并为从植物中提取化学物质或从石化产品中合成化学物质提供可持续的替代方案，从而使加拿大学术界和公共部门受益。＊＊＊＊＊