Dynamic control in metabolic engineering: Theories, tools, and applications

Abstract

Metabolic engineering has allowed the production of a diverse number of valuable chemicals using microbial organisms. Many biological challenges for improving bio-production exist which limit performance and slow the commercialization of metabolically engineered systems. Dynamic metabolic engineering is a rapidly developing field that seeks to address these challenges through the design of genetically encoded metabolic control systems which allow cells to autonomously adjust their flux in response to their external and internal metabolic state. This review first discusses theoretical works which provide mechanistic insights and design choices for dynamic control systems including two-stage, continuous, and population behavior control strategies. Next, we summarize molecular mechanisms for various sensors and actuators which enable dynamic metabolic control in microbial systems. Finally, important applications of dynamic control to the production of several metabolite products are highlighted, including fatty acids, aromatics, and terpene compounds. Altogether, this review provides a comprehensive overview of the progress, advances, and prospects in the design of dynamic control systems for improved titer, rate, and yield metrics in metabolic engineering.

Designing microbial communities to maximize the thermodynamic driving force for the production of chemicals

“…While the (stoichiometric) feasibility of growth may be demanded when computing the respective intervention strategies, it might be more practical to use two-stage processes, where the strains can first grow before a pure production phase is initiated (e.g. via dynamic metabolic switches [ 52 , 53 ]). This also circumvents possible limitations in the MDF of the production pathway when growth and production are coupled (in our calculations we focused on optimal pathway partitioning for pure product synthesis and did not consider feasibility of growth).…”

Development of a Hyperosmotic Stress Inducible Gene Expression System by Engineering the MtrA/MtrB-Dependent NCgl1418 Promoter in Corynebacterium glutamicum

“…Gene expression regulation technologies based on CRISPR and synthetic small RNAs for C. glutamicum have been developed ( Liu et al, 2017 ; Wang et al, 2018 ; Gauttam et al, 2019 ; Sun et al, 2019 ; Li et al, 2020 ). By combining these technologies with metabolic- or QS-responding elements, dynamic regulation strategies have been developed for precise regulation of gene expression to maximize the biosynthesis of target products ( Gupta et al, 2017 ; Chen et al, 2018 ; Shen et al, 2019 ; Liang et al, 2020 ; Tian et al, 2020 ; Hartline et al, 2021 ). However, the metabolic-responding elements are specific for certain metabolites and thus they are not universal for various fermentation processes.…”

Metabolic engineering of Yarrowia lipolytica for terpenoids production: advances and perspectives

“…Dynamic metabolic engineering (DME) is a rapidly developing field that has been applied widely in both E. coli and S. cerevisiae. It allows the cell to autonomously adjust its flux in response to its external and internal metabolic state through the design of genetically encoded metabolic control systems [104]. DME is helpful in improving pathway production and can be further modified and utilized to prevent degenerated and abortive production phenotypes during long-term cultivation and scale-up [105].…”