Canonical Modeling as a Tool in Metabolic Engineering
Voit, Eberhard O.
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A growing branch of metabolic engineering uses mathematical pathway models for the development of strategies for optimizing yield in microbes. The use of such models is necessary because the production pathways are often complex, both in structure and in regulation. For reasons of simplicity, many metabolic engineers use stoichiometric and flux balance models. However, these models ignore cellular regulation. As an alternative, I will discuss canonical models within the modeling framework of Biochemical Systems Theory (BST) as good default representations of fully regulated pathway systems. The presentation will begin with a general introduction to BST, provide some representative examples, and then focus on two questions of optimization. The first concerns the actual optimization of BST models toward yield improvements, which can be formulated as a single linear program or as a series of linear programs. The second type of optimization addresses the de novo design and estimation of BST models from biological data. Of special interest here is the use of in vivo NMR data that characterize time trends in microbial metabolic profiles in a non-invasive fashion. As a specific example I will discuss the production of lactate and other compounds in the bacterium Lactococcus lactis, which is widely used in the food and dairy industry.