Integrating cybernetic modeling with pathway analysis provides a dynamic, systems‐level description of metabolic control

Cybernetic modeling strives to uncover the inbuilt regulatory programs of biological systems and leverage them toward computational prediction of metabolic dynamics. Because of its focus on incorporating the global aims of metabolism, cybernetic modeling provides a systems‐oriented approach for describing regulatory inputs and inferring the impact of regulation within biochemical networks. Combining cybernetic control laws with concepts from metabolic pathway analysis has culminated in a systematic strategy for constructing cybernetic models, which was previously lacking. The newly devised framework relies upon the simultaneous application of local controls that maximize the net flux through each elementary flux mode and global controls that modulate the activities of these modes to optimize the overall nutritional state of the cell. The modeling concepts are illustrated using a simple linear pathway and a larger network representing anaerobic E. coli central metabolism. The E. coli model successfully describes the metabolic shift that occurs upon deleting the pta‐ackA operon that is responsible for fermentative acetate production. The model also furnishes predictions that are consistent with experimental results obtained from additional knockout strains as well as strains expressing heterologous genes. Because of the stabilizing influence of the included control variables, the resulting cybernetic models are more robust and reliable than their predecessors in simulating the network response to imposed genetic and environmental perturbations. Biotechnol. Bioeng. 2008;100: 542–559. © 2008 Wiley Periodicals, Inc.