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The Thermodynamic Meaning of Metabolic Exchange Fluxes

Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland

Correspondence: Address reprint requests to W. Wiechert, E-mail: wiechert{at}simtec.mb.uni-siegen.de.

Metabolic flux analysis (MFA) deals with the experimental determination of steady-state fluxes in metabolic networks. An important feature of the ¹³C MFA method is its capability to generate information on both directions of bidirectional reaction steps given by exchange fluxes. The biological interpretation of these exchange fluxes and their relation to thermodynamic properties of the respective reaction steps has never been systematically investigated. As a central result, it is shown here that for a general class of enzyme reaction mechanisms the quotients of net and exchange fluxes measured by ¹³C MFA are coupled to Gibbs energies of the reaction steps. To establish this relation the concept of apparent flux ratios of enzymatic isotope-labeling networks is introduced and some computing rules for these flux ratios are given. Application of these rules reveals a conceptional pitfall of ¹³C MFA, which is the inherent dependency of measured exchange fluxes on the chosen tracer atom. However, it is shown that this effect can be neglected for typical biochemical reaction steps under physiological conditions. In this situation, the central result can be formulated as a two-sided inequality relating fluxes, pool sizes, and standard Gibbs energies. This relation has far-reaching consequences for metabolic flux analysis, quantitative metabolomics, and network thermodynamics.