The stability and robustness of metabolic states: Elucidating the organization of allosteric regulation in metabolic networks

Dr Ralf Steuer

Humboldt Universitaet zu Berlin, Germany

Cellular Metabolism is a complex dynamical system that is characterized by a tendency to maintain a constant internal state even under strongly varying environmental and intracellular conditions (homeostasis). However, despite significant advances in the structural characterization of metabolic networks, a computational description of these dynamic properties often remains impossible due to the difficulties to formulate detailed kinetic models of cellular pathways.

As an intermediate step between a stoichiometric analysis and explicit models, the talk will describe a simple strategy to elucidate the transition from structure to dynamics of biochemical pathways. We build upon creating a statistical ensemble of possible models that are consistent with given biological and biochemical knowledge. This statistical ensemble then allows for a systematic and quantitative evaluation of the dynamical capabilities of the system.

Using this approach, it is shown that allosteric enzyme regulation can significantly enhance the stability of a metabolic network and may extend its potential dynamic behavior. Moreover, our approach allows to differentiate quantitatively between metabolic states related to senescence and metabolic collapse in a model of the human erythrocyte.

To facilitate analysis of large metabolic networks in the face of lacking or incomplete enzyme-kinetic information, we (i) derive and compare statistical measures for the relative impact of enzymatic reactions and parameters on the dynamic properties (such as local stability), (ii) evaluate the functional role of allosteric feedback regulation in the stabilization of metabolic networks and (iii) propose measures to quantitatively evaluate the stability and robustness properties of metabolic states. We think that the proposed method contributes a step towards formulating genome-scale kinetic models of metabolic networks.

References:

Steuer R, Gross T, Selbig J, Blasius B (2006) Structural kinetic modeling of metabolic networks. Proc Natl Acad Sci USA 103: 11868–11873

Grimbs S, Selbig J, Bulik S, Holzhuetter H-G, Steuer R, (2007) The stability and robustness of metabolic states: identifying stabilizing sites in metabolic networks. Molecular Systems Biology 3: 146:10.1038/msb4100186

Steuer R. (2007) Computational approaches to the topology, stability and dynamics of metabolic networks. Phytochemistry, 2007, doi:10.1016/j.phytochem.2007.04.041

Steuer R, Nunes Nesi A, Fernie AR, Gross T, Blasius B, Selbig J. (2007) From Structure to Dynamics of Metabolic Pathways: Application to the Plant Mitochondrial TCA Cycle. Bioinformatics, doi:10.1093/bioinformatics/btm065