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

1605357/1605877Da Silva，Nancy A.聚酮衍生的天然产物代表了一类重要的药物，其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，聚酮化合物由于其合成和结构的灵活性，作为可再生化学品和燃料也具有吸引力。这项研究将工程酵母酿酒酵母高水平合成聚酮化合物，导致新的方法可持续生产化学品和药品。这项研究还将有助于发现新的酶和生物化学物质。这项研究将通过提供新的、可再生的方法来生产各种商业上重要的化合物，从而影响该领域。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，因此将为多个领域的学生培训提供充足的机会。 聚酮化合物是微生物和植物的代谢产物，对人类健康有重要影响。它们在细菌、真菌和植物中通过聚酮酶从简单的初级代谢物结构单元如乙酰辅酶A和丙二酰辅酶A合成。 随着越来越多的基因组序列变得可用，并且对聚酮化合物生物合成的理解不断增长，在模式生物如酿酒酵母中工程化这些化合物的生产具有重要的机会。本研究将联合收割机聚酮化合物化学与酵母代谢工程相结合，使酵母菌成为高水平生产各种有价值的真菌和植物聚酮化合物的宿主。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前体的能力，以及大量表达瓶颈、限速聚酮脱氢酶的能力。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）生物化学构件和生物表面活性剂;以及iii）从测序真菌物种的基因组挖掘中发现的新化合物。这种整合的方法将导致酵母异源宿主是强大的，通用的和下降的聚酮化合物生产，并可以揭示酵母代谢和优化外源（和困难）蛋白质表达的见解。利用各种聚酮酶进行生物化学生产的工作可以实现增值化学品的可再生生产，以及检查相应聚酮酶的灵活性。该奖项由CBET部门的生物技术和生物化学工程项目共同资助，由材料研究部门的生物材料项目共同资助。

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.