Combining metabolic engineering and synthetic biology to engineer natural product synthesis in oleaginous yeast

结合代谢工程和合成生物学来设计产油酵母中的天然产物合成

• 批准号: 1805139
• 负责人: Philip Farabaugh
• 金额: $ 29.83万
• 依托单位: University of Maryland Baltimore County
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1805139&HistoricalAwards=false
• 关键词: Combining; metabolic; engineering; synthetic; biology

Plants produce chemicals with medicinal properties. Isolating plant natural products (PNPs) from native sources is difficult due to low concentrations. Chemical synthesis is often not economical because of the structural complexity of PNPs. This project will modify yeast to produce a PNP with anti-cancer properties. This molecule represents a class of PNPs with therapeutic value. If yeast can produce high concentrations of PNPs, these drugs could become more affordable. Outreach activities are also planned. Research opportunities will be offered to minority undergraduates. Teaching demonstrations and science fair presentations will be made in Baltimore and the DC area. The goal of these efforts will be to recruit female high school students and underrepresented minorities to pursue STEM careers. To improve the cost-competitiveness of PNP production, the project will address cofactor balance (ATP, NADPH, CoASH et al) and maximize the carbon flow and electron reduction efficiency towards the target pathway. This interdisciplinary approach combines genetic engineering, gene regulation, adaptive lab evolution, tolerance phenotyping, metabolic profiling, and cellular compartmentalization engineering. Biochemical and genetic strategies will abolish HMG-CoA pathway negative feedback control, improve metabolite trafficking, and overexpress plant P450 enzymes. These efforts should improve pathway efficiency and diversify the chemical structure of PNPs. Our strategy will target pathway yield and the total cost of manufacturing. The goal is to build a cost-competitive cyclic triterpenoids biomanufacturing platform with significantly reduced manufacturing cost. This project will provide a testbed for engineering Y. lipolytica and expanding nature's capacity to produce complex PNPs with pharmaceutical values for clinical trials and treating emerging diseases.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

植物产生具有药用特性的化学物质。从天然来源中分离植物天然产物（PNPs）由于浓度低是困难的。由于pnp结构复杂，化学合成往往不经济。该项目将对酵母进行修饰，以产生具有抗癌特性的PNP。该分子代表了一类具有治疗价值的PNPs。如果酵母菌可以产生高浓度的PNPs，这些药物可能会变得更便宜。还计划了外联活动。为少数民族本科生提供研究机会。教学演示和科学展览将在巴尔的摩和华盛顿特区进行。这些努力的目标是招募女高中生和未被充分代表的少数民族从事STEM职业。为了提高PNP生产的成本竞争力，该项目将解决辅因子平衡（ATP， NADPH， CoASH等），并最大限度地提高碳流和电子对目标途径的还原效率。这种跨学科的方法结合了基因工程、基因调控、适应性实验室进化、耐受性表型、代谢谱和细胞区隔化工程。生化和遗传策略将消除HMG-CoA通路的负反馈控制，改善代谢物运输，并过度表达植物P450酶。这些努力将提高途径效率，使PNPs的化学结构多样化。我们的战略目标是途径产量和制造总成本。目标是建立一个具有成本竞争力的环三萜生物制造平台，显著降低制造成本。该项目将提供一个试验平台，用于工程化脂质体Y. polytica，并扩大自然界生产具有临床试验和治疗新发疾病的药物价值的复杂pnp的能力。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Modeling transcriptional factor cross-talk to understand parabolic kinetics, bimodal gene expression and retroactivity in biosensor design

• DOI: 10.1016/j.bej.2019.02.005
• 发表时间: 2019-04
• 期刊: Biochemical Engineering Journal
• 影响因子: 3.9
• 作者: Hannah Aris;Shayan G. Borhani;Devorah Cahn;C. ODonnell;E. Tan;Peng Xu

Engineering metabolite-responsive transcriptional factors to sense small molecules in eukaryotes: current state and perspectives

• DOI: 10.1186/s12934-019-1111-3
• 发表时间: 2019-03
• 期刊: Microbial Cell Factories
• 影响因子: 6.4
• 作者: Xiaoyun Wan;Monireh Marsafari;Peng Xu

Optimizing Oleaginous Yeast Cell Factories for Flavonoids and Hydroxylated Flavonoids Biosynthesis

• DOI: 10.1021/acssynbio.9b00193
• 发表时间: 2019-11-01
• 期刊: ACS SYNTHETIC BIOLOGY
• 影响因子: 4.7
• 作者: Lv, Yongkun;Marsafari, Monireh;Xu, Peng
• 通讯作者: Xu, Peng

Debottlenecking mevalonate pathway for antimalarial drug precursor amorphadiene biosynthesis in Yarrowia lipolytica

• DOI: 10.1016/j.mec.2019.e00121
• 发表时间: 2020-06-01
• 期刊: METABOLIC ENGINEERING COMMUNICATIONS
• 影响因子: 5.2
• 作者: Marsafari, Monireh;Xu, Peng
• 通讯作者: Xu, Peng

Engineering acetyl-CoA metabolic shortcut for eco-friendly production of polyketides triacetic acid lactone in Yarrowia lipolytica

• DOI: 10.1016/j.ymben.2019.08.017
• 发表时间: 2019-12-01
• 期刊: METABOLIC ENGINEERING
• 影响因子: 8.4
• 作者: Liu, Huan;Marsafari, Monireh;Xu, Peng
• 通讯作者: Xu, Peng