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

1605357/1605877Da Silva，Nancy A./Tang，亿聚酮衍生的天然产物代表了一类重要的药物，几乎应用于人类所有主要类型的疾病，包括抗生素、抗癌和抗高胆固醇血症。近年来，聚酮类化合物由于其合成和结构上的灵活性，作为可再生化学品和燃料也具有很大的吸引力。这项研究将对酿酒酵母进行工程改造，使其能够高水平地合成聚酮，从而为化学品和药物的可持续生产带来新的方法。这项研究还将使发现新的酶和生物化学物质成为可能。这项研究将通过提供生产各种具有商业重要性的化合物的新的、可再生的方法来影响该领域。从教育和推广的角度来看，这项研究将跨越工程、化学和生物等核心学科，因此将为学生在多个领域提供充足的培训机会。聚酮类化合物是严重影响人类健康的微生物和植物代谢产物。它们在细菌、真菌和植物中通过聚酮合成酶从简单的初级代谢物构建块如乙酰辅酶A和丙二酰辅酶A合成。随着更多的基因组序列的获得和对聚酮生物合成的了解的加深，在酿酒酵母等模式生物中设计这些化合物的生产有重要的机会。这项研究将聚酮化学和酵母代谢工程结合起来，使酵母成为不同有价值的真菌和植物聚酮的高水平生产宿主。最先进的合成生物学和遗传工具将被用来优化酵母供应聚酮前体的能力，以及大量表达瓶颈、限速的聚酮合成酶。工程酵母将用于生产三组聚酮化合物：i)来自真菌王国的具有治疗价值的化合物；ii)生化构建块和生物表面活性剂；以及iii)通过对已测序的真菌物种进行基因组挖掘而发现的科学新化合物。这种综合的方法将导致酵母异源宿主是强大的，通用的和临时的聚酮生产，并可以揭示酵母的新陈代谢和外源(和困难的)蛋白质表达的优化。使用各种聚酮合成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，并检查相应聚酮合成酶的灵巧性。该奖项由CBET部门的生物技术和生化工程计划获得，由材料研究部的生物材料计划共同资助。

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.