European Molecular Biology Laboratory, EMBL, Heidelberg, Germany.
Department of Bioprocess Engineering, Lodz University of Technology, Poland.
Sci Rep. 2016 Jul 19;6:29694. doi: 10.1038/srep29694.
The diversity of industrially important molecules for which microbial production routes have been experimentally demonstrated is rapidly increasing. The development of economically viable producer cells is, however, lagging behind, as it requires substantial engineering of the host metabolism. A chassis strain suitable for production of a range of molecules is therefore highly sought after but remains elusive. Here, we propose a genome-scale metabolic modeling approach to design chassis strains of Saccharomyces cerevisiae - a widely used microbial cell factory. For a group of 29 products covering a broad range of biochemistry and applications, we identified modular metabolic engineering strategies for re-routing carbon flux towards the desired product. We find distinct product families with shared targets forming the basis for the corresponding chassis cells. The design strategies include overexpression targets that group products by similarity in precursor and cofactor requirements, as well as gene deletion strategies for growth-product coupling that lead to non-intuitive product groups. Our results reveal the extent and the nature of flux re-routing necessary for producing a diverse range of products in a widely used cell factory and provide blueprints for constructing pre-optimized chassis strains.
已经有实验证明，微生物生产途径可以生产出多种多样的工业用重要分子。然而，经济可行的生产细胞的开发却滞后了，因为这需要对宿主代谢进行大量的工程改造。因此，人们非常需要一种适合生产多种分子的底盘菌株，但这种菌株仍然难以捉摸。在这里，我们提出了一种基于基因组规模代谢建模的方法来设计酿酒酵母（一种广泛使用的微生物细胞工厂）的底盘菌株。对于涵盖广泛生物化学和应用的 29 种产品，我们确定了模块化的代谢工程策略，以重新分配碳通量以生产所需的产品。我们发现具有共享目标的不同产品家族为相应的底盘细胞奠定了基础。这些设计策略包括根据前体和辅因子需求的相似性进行过表达的目标，以及用于生长-产物偶联的基因缺失策略，这些策略导致了非直观的产物群。我们的研究结果揭示了在广泛使用的细胞工厂中生产多种产品所需的通量重定向的程度和性质，并为构建预优化的底盘菌株提供了蓝图。
