Dynamic strain scanning optimization: an efficient strain design strategy for balanced yield, titer, and productivity. DySScO strategy for strain design

Abstract

BackgroundIn recent years, constraint-based metabolic models have emerged as an important tool for metabolic engineering; a number of computational algorithms have been developed for identifying metabolic engineering strategies where the production of the desired chemical is coupled with the growth of the organism. A caveat of the existing algorithms is that they do not take the bioprocess into consideration; as a result, while the product yield can be optimized using these algorithms, the product titer and productivity cannot be optimized. In order to address this issue, we developed the Dynamic Strain Scanning Optimization (DySScO) strategy, which integrates the Dynamic Flux Balance Analysis (dFBA) method with existing strain algorithms.ResultsIn order to demonstrate the effective of the DySScO strategy, we applied this strategy to the design of Escherichia coli strains targeted for succinate and 1,4-butanediol production respectively. We evaluated consequences of the tradeoff between growth yield and product yield with respect to titer and productivity, and showed that the DySScO strategy is capable of producing strains that balance the product yield, titer, and productivity. In addition, we evaluated the economic viability of the designed strain, and showed that the economic performance of a strain can be strongly affected by the price difference between the product and the feedstock.ConclusionOur study demonstrated that the DySScO strategy is a useful computational tool for designing microbial strains with balanced yield, titer, and productivity, and has potential applications in evaluating the economic performance of the design strains.

Manipulation of the ATP pool as a tool for metabolic engineering

“…Typically, a non-linear relationship between the analysed process parameters can be seen whose exact shape depends on concrete parameter values (for a detailed mathematical analysis see [3]). …”

“…Such a shift can only be successful if the designed processes are not only advantageous with respect to environmental issues but at least as economically viable as their petrochemical counterparts [1,2]. Key parameters that determine the quality of production processes with respect to economical needs are product yield, product titre and productivity [3,4].…”

Identification of metabolic engineering targets for the enhancement of 1,4-butanediol production in recombinant E. coli using large-scale kinetic models

“…NADH/NAD + and NADPH/NADP ratios, are important markers when considering strategies for metabolic engineering of an organism (Moreira dos Santos et al, 2003;Pitkanen et al, 2003;Thomas et al, 2007). In particular, increased redox potential is considered as an important factor in improving BDO production in (Zhuang et al, 2013).…”

“…Increasing PPC activity could also lead to increased flux through the reductive TCA cycle, which would consume reducing equivalents; therefore it is negatively correlated with redox potential. Zhuang et al predicted that increased activity of enzymes in the BDO production pathway would give higher BDO production, but it would be at the expense of the lower growth rate due to NADPH depletion (Zhuang et al, 2013).…”

Computer-Guided Metabolic Engineering

“…This can be done by combining existing in silico strain optimization algorithms with dynamic flux balance analysis [23,57,58] to optimize yield (Y), titer (T), and productivity (P) in a balanced fashion. Zhuang [59] presented a Dynamic Strain Scanning Optimization (DySScO) strategy that uses this rationale to produce strains that balance the product yield, titer, and productivity. DySScO searches for a strain design that maximizes a userdefined metric of the form: Z ¼ f(Y, T, P).…”