Collaborative Research: SusChEM: A Robust Yeast Platform for the Synthesis and Engineering of Polyketide-Based Pharmaceuticals and Chemicals

合作研究：SusChEM：用于聚酮化合物药物和化学品合成和工程的强大酵母平台

• 批准号: 1605357
• 负责人: Nancy Da Silva
• 金额: $ 30万
• 依托单位: University of California-Irvine
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1605357&HistoricalAwards=false
• 关键词: Collaborative; Research; SusChEM; Robust; Yeast

1605357/1605877Da Silva, Nancy A./Tang, YiPolyketide-derived natural products represent an important class of pharmaceuticals with application to nearly all major types of human diseases, including antibiotics, anticancer, and anti-hypercholesterolemia. In recent years, polyketides have also been attractive as renewable chemicals and fuels, due to the flexibility in their synthesis and their structures. This research will engineer the yeast Saccharomyces cerevisiae for the high-level synthesis of polyketides, leading to new methods for the sustainable production of chemicals and pharmaceuticals. The research will also enable the discovery of new enzymes and biochemicals. The research will impact the field by providing new, renewable ways of producing a variety of commercially important compounds. From an educational and outreach perspective, the research will span the core disciplines of engineering, chemistry and biology, and will therefore provide ample opportunities for student training in multiple areas. Polyketides are microbial and plant metabolites that have significantly impacted human health. They are synthesized in bacteria, fungi and plants by polyketide synthases from simple primary metabolite building blocks such as acetyl-CoA and malonyl-CoA. As more genome sequences have become available and understanding of polyketide biosynthesis grows, there are significant opportunities to engineer the production of these compounds in model organisms such as Saccharomyces cerevisiae. This research will combine polyketide chemistry and yeast metabolic engineering to outfit yeast as a high-level production host for different valuable fungal and plant polyketides. State of the art synthetic biology and genetic tools will be used to optimize the capacity of yeast to supply the polyketide precursors, as well as to abundantly express the bottleneck, rate-limiting polyketide synthases. The engineered yeast will be applied towards the production of three sets of polyketide compounds: i) compounds of therapeutic values from the fungal kingdom; ii) biochemical building blocks and biosurfactants; and iii) novel compounds new to science discovered from genome mining of sequenced fungal species. This integrated approach will lead to yeast heterologous hosts that are powerful, general and drop-in for polyketide production, and can reveal insights into yeast metabolism and optimization of foreign (and difficult) protein expression. The work on biochemical production using various polyketide synthases can enable renewable production of value added chemicals, as well as examine the dexterity of corresponding polyketide synthases.This award by the Biotechnology and Biochemical Engineering Program of the CBET Division is co-funded by the Biomaterials Program of the Division of Materials Research.

1605357/1605877Da Silva, Nancy A./Tang, Yi 聚酮化合物衍生的天然产物代表了一类重要的药物，可应用于几乎所有主要类型的人类疾病，包括抗生素、抗癌和抗高胆固醇血症。近年来，由于其合成和结构的灵活性，聚酮化合物作为可再生化学品和燃料也很有吸引力。这项研究将改造酿酒酵母，用于高水平合成聚酮化合物，从而为化学品和药品的可持续生产提供新方法。该研究还将有助于发现新的酶和生化物质。该研究将通过提供生产各种具有商业价值的化合物的新的、可再生的方法来影响该领域。从教育和推广的角度来看，该研究将跨越工程、化学和生物学的核心学科，因此将为学生在多个领域的培训提供充足的机会。 聚酮化合物是对人类健康有重大影响的微生物和植物代谢物。它们是在细菌、真菌和植物中通过聚酮合酶从简单的初级代谢产物结构单元（例如乙酰辅酶A和丙二酰辅酶A）合成的。 随着越来越多的基因组序列的出现以及对聚酮化合物生物合成的了解的不断加深，在酿酒酵母等模型生物体中改造这些化合物的生产有很大的机会。这项研究将结合聚酮化合物化学和酵母代谢工程，使酵母成为不同有价值的真菌和植物聚酮化合物的高水平生产宿主。最先进的合成生物学和遗传工具将用于优化酵母提供聚酮化合物前体的能力，以及充分表达瓶颈限速聚酮化合物合酶。工程酵母将用于生产三组聚酮化合物：i）来自真菌界的具有治疗价值的化合物； ii) 生化构件和生物表面活性剂； iii) 通过对已测序真菌物种的基因组挖掘发现的科学新化合物。这种综合方法将产生强大的、通用的、可直接用于聚酮化合物生产的酵母异源宿主，并且可以揭示对酵母代谢和外来（和困难）蛋白质表达的优化的见解。使用各种聚酮合酶进行生化生产的工作可以实现增值化学品的可再生生产，并检查相应聚酮合酶的灵巧性。该奖项由 CBET 部门生物技术和生化工程项目与生物材料项目共同资助材料研究部。