Seminars & Events
Mathematics and Computer Science Division Seminar
"Application of Thermodynamic Constraints to Metabolic Flux Analysis"
DATE: January 24, 2007
TIME: 10:30am
SPEAKER: Christopher Henry, Northwestern University
LOCATION: Bldg: 221, Conference Room A216, Argonne National Laboratory
HOST: Rick Stevens
Description:
Metabolic flux analysis (MFA) has developed into one of the prevailing tools for predicting the flux through intracellular reactions, testing the stoichiometry of metabolic models, predicting and explaining the phenotypic behavior of microorganisms, and providing guidance for the metabolic engineering of microorganisms. However, standard forms of MFA suffer from two disadvantages: (i) some of the flux distributions predicted using MFA will be thermodynamically infeasible, and (ii) no information on the reaction driving force or the metabolite concentrations is provided. One way of simultaneously overcoming both of these disadvantages is to use thermodynamic constraints in addition to the mass balance constraints of MFA.
The formulation of thermodynamic constraints for a metabolic model requires knowledge of the standard Gibbs free energy change (.rG��) for the reactions in the model. In the first portion of my talk I will discuss the application of the group contribution method (Jankowski, Henry et al.; Benson 1968; Mavrovouniotis 1990) for estimating the standard Gibbs free energy change of reaction (.rG��) for 96% of the reactions involved in a genome-scale metabolic model of Escherichia Coli (Henry, Jankowski et al. 2006). In contrast, experimentally observed .rG�� values are available for only 5.6% of the reactions in the E. coli model. Based on these .rG�� estimates, over 21% of the reactions in the model were found to exist close to equilibrium under physiological conditions.
Once the .rG�� for most of the reactions in the model have been measured or estimated, thermodynamic constraints can be written for the reactions in the model. In the second portion of my talk, I will discuss our development of Thermodynamics-based Metabolic Flux Analysis (TMFA) (Henry 2007). TMFA involves the use of a set of linear thermodynamic constraints in addition to the mass balance constraints typically used for predicting the flux through the intracellular reactions of a cell. TMFA produces flux distribution predictions that do not contain any thermodynamically infeasible reactions or pathways, and it provides information about the free energy change of reactions and the
ranges of metabolite activities. The results of a TMFA performed on a genome-scale model of E. coli indicate that the metabolite activities and reaction .rG' can achieve a wide range of values during optimal cell growth. However, when studying the thermodynamically feasible ranges for ratios of metabolite activities we find that the NAD/NADH and NADP/NADPH ratios maintained in the cell are close to the minimum feasible ratio and maximum feasible ratio, respectively.
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