The dynamics of metabolic regulation
Cellular metabolism is a complex network of biochemical reactions, whose regulation enables living cells to cope with variable environments and perturbations. Since metabolic regulation occurs at multiple time scales and involves diverse molecular mechanisms, understanding and manipulating the dynamics of metabolism in the cell constitutes an open challenge in systems biology. The work presented in this dissertation explores the coupled dynamics of metabolism and regulatory control using different theoretical and computational approaches. First, I frame my work from the perspective of the multiple time scales along which regulatory processes unfold. In particular, I present three increasingly complex models of coupled metabolic-regulatory dynamics, ranging from single biochemical reactions, to a small hybrid metabolic-genetic oscillator, and finally to an entire genome-scale metabolic network. To deconvolve the distinct roles of metabolism and regulation in these models, I apply some classical tools from physics (variational calculus) and operations research (optimization theory). The results shed light on the interdependent role of structure and function in the design of metabolic systems, as well as on the contemporary challenge of integrating high-throughput data with complex metabolic models. Next, I focus on the question of whether and how metabolic dynamics may be inferred directly from the architecture of the metabolic network itself, irrespective of regulation. In one project, I prove that the structure of a class of metabolic cycles endows them with stable equilibria, regardless of the choice of rate laws or kinetic parameters. A curious outcome of this proof are two theorems describing the location of the roots of a sum of polynomials. In a second project, I use high-throughput metabolomics data and the notion of flux imbalances in stoichiometric models of metabolism to calculate quantitative measures of growth-limitation. I then use these quantities to grossly describe the dynamics of intracellular metabolites following a perturbation. Taken together, my results suggest possible routes for identifying fundamental principles of biological organization which may guide future efforts in metabolic engineering and synthetic biology.
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