Metabolic Engineering in the -omics Era: Elucidating and Modulating Regulatory Networks

Abstract

The importance of regulatory control in metabolic processes is widely acknowledged, and several enquiries (both local and global) are being made in understanding regulation at various levels of the metabolic hierarchy. The wealth of biological information has enabled identifying the individual components (genes, proteins, and metabolites) of a biological system, and we are now in a position to understand the interactions between these components. Since phenotype is the net result of these interactions, it is immensely important to elucidate them not only for an integrated understanding of physiology, but also for practical applications of using biological systems as cell factories. We present some of the recent “-omics” approaches that have expanded our understanding of regulation at the gene, protein, and metabolite level, followed by analysis of the impact of this progress on the advancement of metabolic engineering. Although this review is by no means exhaustive, we attempt to convey our ideology that combining global information from various levels of metabolic hierarchy is absolutely essential in understanding and subsequently predicting the relationship between changes in gene expression and the resulting phenotype. The ultimate aim of this review is to provide metabolic engineers with an overview of recent advances in complementary aspects of regulation at the gene, protein, and metabolite level and those involved in fundamental research with potential hurdles in the path to implementing their discoveries in practical applications

Ethanol synthesis from glycerol by Escherichia coli redox mutants expressing adhE from Leuconostoc mesenteroides

“…Besides, environmental deterioration resulting from over-consumption of petroleumderived products could eventually threat human society sustainability (Demain 2009). Metabolic engineering of biological pathways for the synthesis of industrial chemicals offers an interesting alternative to fossil fuels and petroleum-derived chemicals (Vemuri and Aristidou 2005). Ethanol has potential as a biofuel and feedstock for the production of oxygenated fuels, having a positive environmental impact because of its low-polluting combustion (Stephanopoulos et al 1998).…”

Engineering of the methylmalonyl-CoA metabolite node of Saccharopolyspora erythraea for increased erythromycin production

“…This process is performed in a step-wise fashion in an industrial organism where strain improvement mutations and corresponding process enhancements are added sequentially. The method of screening directly for the desired phenotype followed by reverse engineering generates high-quality targets that can then be further exploited by "omic" analyses and metabolic engineering (Vemuri and Aristidou, 2005).…”

Industrial systems biology

“…Although this methodology has endured tremendous success, it has largely been end-product driven with minimal mechanistic understanding. Today, with the exponential increase in genome sequences of existing and future production hosts, coupled with tools from bioinformatics that enable integration and interrogation of x-omic data sets, it is possible to identify high-probability targeted genetic strategies to increase yield, titer, productivity, and/or robustness (Patil et al, 2004;Stephanopoulos, 1999;Vemuri and Aristidou, 2005). It is also now possible to perform inverse or reverse metabolic engineering, where previously successful production systems may be x-omically characterized to elucidate key metabolic pathways and control points for future rounds of targeted metabolic engineering (Bro and Nielsen, 2004;Otero et al, 2007).…”