(533e) A Pareto Optimality Explanation of the Glycolytic Pathways in Nature

The Entner-Doudoroff (ED) and Embden-Meyerhof-Parnas (EMP) glycolytic pathways are generally well-conserved across saccharolytic species in all three domains of life (i.e. Eukarya, Bacteria and Archaea). Although both pathways convert glucose to pyruvate, reactions constituting these two pathways span different intermediates resulting in varying ATP yields for different organisms. One could construct a multiple of possible ways of converting glucose to pyruvate with sometimes higher ATP yield. This raises the question as to why nature generally employs either EMP or ED glycolysis. Is this a coincidence, convergent evolution or there exists a driving force towards either of the two pathway designs? We addressed this question by first employing the loopless-optStoic algorithm to prospect for multiple possible pathways between glucose and pyruvate at different pre-determined stoichiometric yields of ATP (i.e., from 0.5 to 5 mol ATP/mol glucose). Subsequently, we analyzed the thermodynamic feasibility of all the pathways at physiological metabolite concentrations and quantified the protein cost of the feasible solutions. We identified the pareto optima for the trade-off between energy efficiency and protein cost for each of the feasible routes. Interestingly, we found that both the naturally evolved ED and EMP pathways are among the most protein cost-efficient pathways when compared to other pathways generating one and two mol ATP/mol glucose, respectively. Although at standard conditions, conversion of glucose to pyruvate could generate up to 5 mol ATP/mol glucose with favorable thermodynamic driving force (Î?_rG° < 0), we found that most pathways designed for higher ATP production (> 2 ATP) are thermodynamically infeasible at physiological metabolite concentration ranges. In addition, while there exist several thermodynamically feasible pathways with up to 3 ATP production, they required approximately 4-fold higher investment on catalytic machinery to drive the pathway flux, which provides one possible explanation why these high ATP-yielding pathways are not found in nature.