Metabolic engineering from a cybernetic perspective: aspartate family of amino acids

Using the modular cybernetic framework developed by Varner and Ramkrishna (Varner and Ramkrishna; 1998a, b) a cybernetic model is formulated that describes the time evolution of the aspartate family of amino acids in Corynebacterium lactofermentum ATCC 21799. The network model formulation is employed in the role of a diagnostic tool for the overproduction of threonine. More precisely, having determined a parameter set that describes the time evolution of a base strain (lysine producer), the model predicted response to genetic perturbations, designed to enhance the level of threonine, are simulated using an appropriately modified cybernetic model and compared with the experimental results of Stephanopoulos and Sinskey (Colón et al., 1995a, Appl. Environ. Microbiol. 61, 74-78) for identical genetic perturbations. It is found that the model predicted response to enzymatic over-expression in the aspartate pathway agrees, for the most part, with experimental observations within the experimental error bounds. This result lends credence to the hypothesis that cybernetic models can be employed to predict the local response of a metabolic network to genetic perturbation, thereby, affording cognizance of the potential pitfalls of a particular genetic alteration strategy a priori.