Plant terpenoids: Deciphering metabolic pathways and improving production in microbes

植物萜类化合物：破译代谢途径并提高微生物的产量

基本信息

批准号：
10714595
负责人：
Zhen Wang
金额：
$ 39.88万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

项目摘要

Beyond their prevalence in everyday life, many plant terpenoids have life-saving medicinal applications for a variety of human diseases. Despite their clear medicinal importance, it remains unclear how plants synthesize most plant terpneoids. This knowledge gap prevents us from developing a better method to access terpenoids since medicinal terpenoids are extracted from plants with meager yields. This research program aims to accelerate the identification of plant terpenoid biosynthetic pathways and to improve plant terpenoid production in microbes. Synthesizing plant terpenoids in microbes is a far more cost-effective approach as it can significantly enhance terpenoid productivity and shorten production time. We developed an integrated workflow capable of high-throughput characterization of multiple plant terpenoid pathways in parallel. This workflow combines genomic mining, transcriptomic analysis, metabolomics, and biochemical assays for terpenoid pathway elucidation followed by pathway reconstitution in engineered microbes for high-titer terpenoid production. Our workflow is unique in that it includes gene clusters in plant genomes as an untapped source for uncovering novel plant biosynthetic pathways. Another unique feature of our workflow is that we use a highly engineered yeast strain as a platform to produce plant specialized terpenoids. This highly productive platform strain sets the stage for cost-effective production of any of the >80,000 terpenoids and infinite numbers of terpenoid analogs. In this research program, we will apply this workflow to decipher multiple plant terpenoid pathways, including valuable mono-, di-, sesqui-, tri-, and tetra-terpenoid synthetic routes in foxglove, millet, crocus, and other plant species. Progress from the proposed work will advance fundamental knowledge regarding how plants synthesize medicinally important or biologically active terpenoids. It will also transform the biomanufacturing of plant-based medicines for renewable and cost-effective production.

除了在日常生活中普遍存在之外，许多植物萜类化合物还具有拯救生命的医学应用各种人类疾病。尽管它们具有明显的药用价值，但仍不清楚植物如何合成大多数植物萜类化合物。这种知识差距阻止我们开发更好的方法来获取萜类化合物由于药用萜类化合物是从植物中提取的，产量微薄。该研究计划旨在加速植物萜类化合物生物合成途径的鉴定并提高植物萜类化合物的产量在微生物中。在微生物中合成植物萜类化合物是一种更具成本效益的方法，因为它可以显着提高萜类化合物的生产率，缩短生产时间。我们开发了一个集成的工作流程，能够多个植物萜类化合物途径的并行高通量表征。该工作流程结合了萜类化合物途径的基因组挖掘、转录组分析、代谢组学和生化分析阐明，然后在工程微生物中重建用于高滴度萜类化合物生产的途径。我们的工作流程的独特之处在于它包括植物基因组中的基因簇作为发现新奇的未开发来源植物生物合成途径。我们工作流程的另一个独特之处是我们使用高度工程化的酵母菌株作为生产植物专用萜类化合物的平台。这种高生产力的平台菌株奠定了基础用于经济高效地生产超过 80,000 种萜类化合物和无限数量的萜类化合物类似物。在这个研究计划中，我们将应用此工作流程来破译多种植物萜类途径，包括有价值的毛地黄、小米、番红花和其他植物物种中的单萜、二萜、倍半萜、三萜和四萜合成途径。拟议工作的进展将推进有关植物如何合成的基础知识具有药用价值或生物活性的萜类化合物。它还将改变植物基生物制造用于可再生且具有成本效益的生产的药物。