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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=715569
• 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。