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Biophys. J. BioFAST: First Published December 15, 2006. doi:10.1529/biophysj.106.093138
© 2006 by the Biophysical Society.

A more recent version of this article appeared on March 1, 2007.
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BIOENERGETICS

Thermodynamics-based Metabolic Flux Analysis

Christopher S. Henry 1, Linda J. Broadbelt 1 and Vassily Hatzimanikatis 2*

1 Northwestern University
2 EPFL

* To whom correspondence should be addressed. E-mail: vassily{at}northwestern.edu.

Submitted on September 27, 2006
Revised on November 1, 2006
Accepted on 3 November 2006


  Abstract
A new form of metabolic flux analysis (MFA) called thermodynamics-based metabolic flux analysis (TMFA) is introduced with the capability of generating thermodynamically feasible flux and metabolite activity profiles on a genome scale. TMFA involves the use of a set of linear thermodynamic constraints in addition to the mass balance constraints typically used in MFA. TMFA produces flux distributions that do not contain any thermodynamically infeasible reactions or pathways, and it provides information about the free energy change of reactions and the range of metabolite activities in addition to reaction fluxes. TMFA is applied to study the thermodynamically feasible ranges for the fluxes and the Gibbs free energy change, rG', of the reactions and the activities of the metabolites in the genome-scale metabolic model of E. coli, iJR904 (1). In the TMFA of the genome scale model, the metabolite activities and reaction are able to achieve a wide range of values at optimal growth. The reaction dihydrooratase is identified as a possible thermodynamic bottleneck in E. coli metabolism with a rG' constrained close to zero while numerous reactions are identified throughout metabolism for which rG' is always highly negative regardless of metabolite concentrations. As it has been proposed previously, these reactions with exclusively negative rG' might be candidates for cell regulation (2), and we find that a significant number of these reactions appear to be the first steps in the linear portion of numerous biosynthesis pathways. The thermodynamically feasible ranges for the concentration ratios ATP/ADP, NAD(P)/NAD(P)H, and H+extracellular/H+intracellular are also determined and found to encompass the values observed experimentally in every case. Further, 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.

Key Words: E. coli, concentration profile, genome scale, group contribution method, metabolic flux analysis, thermodynamics




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Copyright © 2006 by the Biophysical Society.