Synthetic Biology of Yeast

智力优势：酿酒酵母是生产日用化学品、燃料和蛋白质的最广泛使用的微生物之一。这项研究将开发酵母的遗传、计算机辅助设计和菌株工程工具，并将展示它们在表达用于生产重要化学品的多组分聚酮合成酶方面的用途。选择将酵母工程用于聚酮合成是因为最有用的天然产品是聚酮，所涉及的生物合成酶可以被改造成生产广泛的药品、商品和特种化学品以及燃料。功能性聚酮合成酶的表达和提供生物合成机制所需的前体的生产是一个具有挑战性的问题，需要更好的生物宿主和适当的基因表达工具。该项目的具体目标是：1)开发快速修改酿酒酵母基因组的通用方法，以创建能够在极端条件下生长和/或生存的酵母菌株的改良版本；2)创建一套基因表达控制设备，并展示其对生产特定商品化学品所需的聚酮合成酶复合体的效用；3)构建聚酮前体的合成途径；4)创建用于生产各种化学品的聚酮合成酶文库；以及5)开发能够快速构建酵母的计算机辅助设计(CAD)软件。更广泛的影响：为合成聚酮开发的工具将广泛适用于酵母工程，以生产各种产品以及探索基础酵母生物学。这项转化研究工作将为一种与工业相关的有机体带来最先进的合成生物学进展。对社会的主要潜在好处将是用来自可再生资源的单体取代现有的石油基聚合物单体；生产用于无法制造的新材料的新型单体；用于科学项目和应用的工程酵母的生物成分；以及用于生物学的计算机辅助设计工具。调查人员将利用合成生物学工程研究中心建立的关系来帮助小公司和大公司发展生物经济。研究人员将利用研究成果在这一新的研究领域教授和培训一批尖端的博士后、研究生和本科生。该项目将通过加州大学伯克利分校和麻省理工学院现有的REU项目来支持人数不足的本科生，并通过SynBERC博士后研究员开发的新高中项目来支持贫困高中生。

Intellectual merit: Saccharomyces cerevisiae (yeast) is one of the most widely used microorganisms for production of commodity chemicals and fuels, and proteins. This research will develop genetic, computer aided design, and strain engineering tools for yeast and will demonstrate their use in expressing multi-component polyketide synthases for the production of important chemicals. The choice to engineer yeast for polyketide synthesis is derived from the fact that the most useful natural products are polyketides and the biosynthetic enzymes involved can be engineered to produce a broad range of pharmaceuticals, commodity and specialty chemicals, and fuels. The expression of functional polyketide synthases and the production of the necessary precursors to supply the biosynthetic machinery is a challenging problem that requires a better biological host and the appropriate gene expression tools. The specific aims of the project are to 1) develop generalized methods for the rapid modification of the S. cerevisiae genome to create modified versions of yeast strains that are capable of growing and/or surviving extreme conditions; 2) create a suite of gene expression control devices and demonstrate their utility for producing polyketide synthase complexes for the production of specific commodity chemicals; 3) construct pathways for the synthesis of polyketide precursors; 4) create libraries of polyketide synthases for production of diverse chemicals; and 5) develop computer aided design (CAD) software that will enable the rapid construction of yeasts. Broader impacts: The tools developed for the synthesis of polyketides will be broadly applicable for the engineering of yeast to produce a variety of products as well as exploring fundamental yeast biology. This translational research effort will bring state-of-the-art synthetic biology advances to an industrially-relevant organism. The major potential benefits to society will be replacement of existing, petroleum-based polymer monomers with monomers derived from renewable resources; production of novel monomers for new materials that cannot be made; biological components for engineering yeast for scientific projects and applications; and computer-aided design tools for biology. The investigators will use relationships developed through the Synthetic Biology Engineering Research Center to help small and large companies grow the bioeconomy. The investigators will use the research findings to teach and train a cutting-edge workforce of post-docs, graduate students, and undergraduate students in this new area of research. The project will support underrepresented undergraduate students through established REU programs at UC Berkeley and MIT, and underprivileged high school students through a novel high school program developed by post-doctoral fellows in SynBERC.