A Dynamic Model of Metabolism That Integrates 13C Isotopomer Data

A Dynamic Model of Metabolism that Integrates ¹³C Isotopomer Data

In the past few years, genome scale metabolic reconstructions based on constraint based modelling have been proven to be a very powerful tool to study the metabolic properties of cells and tissues. However, they have the limitation that they can only provide a static picture of metabolism. The alternative is to use dynamic metabolic models, usually referred to as kinetic models. Kinetic models have two main advantages over constraint based modelling; firstly they are capable of performing dynamic simulations, that is to say, they can predict the variation in metabolite concentrations and fluxes over time outside of the steady state. Secondly, they can follow the global effects of constraints emerging from the specific kinetic properties of enzymes, post-translational modifications and regulatory circuits, thus revealing the complex regulation of the system. The main limitation of kinetic models is that they are complex to build and parametrize. Due to this complexity, kinetic models tend to contain only a small number of reactions. Furthermore, they often assume a constant redox and energy state which limits their application. For instance, despite the key metabolic role of hepatocytes, there are no models capable of adequately modelling the effects of the energy and redox dynamics on hepatocyte core metabolism.

Our group has developed HepatoDyn (Hepatocyte Dynamics), a kinetic model of hepatocyte core metabolism capable of simulating the redox and energy dynamics. The model includes glycolysis, gluconeogenesis, glycogen metabolism, the pentose phosphate pathway, the Krebs cycle and fatty acid metabolism as well as reactions associated with energy and redox metabolism. Furthermore, the model was coupled to the module for isotopic label propagation of the software package IsoDyn allowing it to integrate data from ¹³C based experiments to assist in the parametrization process. Therefore, HepatoDyn is a very powerful tool capable of taking advantage of both the constraints derived from a detailed tissue-specific kinetic model and data derived from ¹³C based experiments to perform metabolic simulations.

Compared to genome scale metabolic models, HepatoDyn has fairly small scope, focusing only on central carbon metabolism. However, we believe one of the applications of our model could be to provide additional constraints to genome scale metabolic models, constraining the solution of space to those solutions that are consistent with the kinetic properties of enzymes and consistent with ¹³C measurements. We believe this could enhance the predictive capacity of genome scale metabolic models.