Metabolic engineering exploits an integrated, systems-level approach for optimizing a desired cellular property or phenotype; and great strides have been made within this scope and context during the past fifteen years. However, due to limitations in the concepts and techniques, these have relied on a focused, pathway-oriented view. Recent advances in 'omics' technologies and computational systems biology have brought the foundational systems approach of metabolic engineering into focus. At the same time, protein engineering and synthetic biology have expanded the breadth and precision of the methods available to metabolic engineers to improve strain properties. Examples are presented that illustrate this broader perspective of tools and concepts, including a recent approach for global transcriptional machinery engineering (gTME), which has demonstrated the ability to elicit multigenic transcriptional changes that have improved phenotypes compared with single-gene perturbations.
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