TOWARDS A MECHANISTIC RELATIONSHIP OF THE RATE/EFFICIENCY TRADE-OFF IN METABOLISM

NIEBEL, B; ZAMPAR, GG; HEINMANN, M

Groningen

Congreso; Mathematical models in ecology and evolution; 2011

Several cells, such as S. cerevisiae, E. coli or mammalian cells, show different metabolic modes dependent on the nutrient uptake rate. With a low glucose uptake rate they tend to respire, while they ferment when the glucose uptake rate is high. The metabolic modes of fermentation and respiration use different catabolic pathways with different ATP generating “efficiencies”. It was often argued that a trade-off exists between “rate” and “efficiency”. Although this trade-off resembles an intuitive concept, the term “efficiency” is only vaguely defined and the true mechanic relationship of this trade-off remains unclear. Here, as a first step towards unraveling the relationship, we first identify a true thermodynamic quantity for “efficiency”. When defining efficiency as the ratio between the ‘entropy production rate per substrate uptake rate’ and ‘the maximum entropy production rate that could be achieved by the same substrate uptake rate’ – with the entropy production rate serving as a measure of the non-equilibrium processes within the cell – we found that this efficiency indeed negatively correlates with the substrate uptake rate in S. cerevisiae in a trade-off manner. Based on this observation, we tested whether thermodynamics are indeed the mechanistic cause for the rate/efficiency trade-off. We used a constraint-based modeling approach, which incorporates the stoichiometry of the metabolism, the second law of thermodynamics and the entropy production rate, to test our hypothesis. As we found the metabolic mode to change from the highly efficient respiration to the less efficient fermentation with increasing glucose uptake rate, we conclude that thermodynamics is indeed the cause for the rate/efficiency trade-off in metabolism.