OP‐Synthetic: identification of optimal genetic manipulations for the overproduction of native and non‐native metabolites

Abstract

Constraint‐based flux analysis has been widely used in metabolic engineering to predict genetic optimization strategies. These methods seek to find genetic manipulations that maximally couple the desired metabolites with the cellular growth objective. However, such framework does n ot work well for overproducing chemicals that are not closely correlated with biomass, for example non‐native biochemical production by introducing synthetic pathways into heterologous host cells. Here, we present a computational method called OP‐Synthetic, which can identify effective manipulations (upregulation, downregulation and deletion of reactions) and produce a step‐by‐step optimization strategy for the overproduction of indigenous and non‐native chemicals. We compared OP‐Synthetic with several state‐of‐the‐art computational approaches on the problems of succinate overproduction and N‐acetylneuraminic acid synthetic pathway optimization in Escherichia coli. OP‐Synthetic showed its advantage for efficiently handling multiple steps optimization problems on genome wide metabolic networks. And more importantly, the optimization strategies predicted by OP‐Synthetic have a better match with existing engineered strains, especially for the engineering of synthetic metabolic pathways for non‐native chemical production. OP‐Synthetic is freely available at: http://bioinfo.au.tsinghua.edu.cn/member/xwwang/OPSynthetic/.