Pathway Thermodynamics Highlights Kinetic Obstacles in Central Metabolism

• DOI: 10.1371/journal.pcbi.1003483
• Publication Date: 2014-02-20T22:03:21Z
• Authors: Elad Noor; Arren Bar-Even; Avi Flamholz; Ed Reznik; Wolfram Liebermei...; Ron Milo
• Keywords: Metabolic pathway

In metabolism research, thermodynamics is usually used to determine the directionality of a reaction or feasibility pathway. However, relationship between thermodynamic potentials and fluxes not limited questions directionality: also affects kinetics reactions through flux-force relationship, which states that logarithm ratio forward reverse directly proportional change in Gibbs energy due (ΔrG'). Accordingly, if an enzyme catalyzes with ΔrG' -5.7 kJ/mol then flux will be roughly ten times flux. As approaches equilibrium (ΔrG' = 0 kJ/mol), exponentially more counterproductively reaction, reducing net rate at proceeds. Thus, level required achieve given increases dramatically near equilibrium. Here, we develop framework for quantifying degree pathways suffer these limitations on For each pathway, calculate single thermodynamically-derived metric (the Max-min Driving Force, MDF), enables objective ranking by their constrained low driving force. Our accounts effect pH, ionic strength metabolite concentration ranges allows us quantify how alterations pathway structure affect pathway's thermodynamics. Applying this methodology central sheds light some features, including metabolic bypasses (e.g., fermentation bypassing substrate-level phosphorylation), substrate channeling oxaloacetate from malate dehydrogenase citrate synthase), use alternative cofactors quinone as electron acceptor instead NAD). The methods presented here place another arrow engineers' quiver, providing simple means evaluating kinetic quality different chemistries produce same molecules.