Trade-off between flux efficiency and metabolic control shapes enzyme allocation

Abstract Efficient use of limited cellular resources is fundamental to metabolism. Although flux optimization is widely recognized as a central objective of metabolic networks, how flux efficiency influences the allocation of the metabolic proteome remains unclear and lacks direct validation. Here, we derive a simple analytical relationship linking the equilibrium constant (K) and the catalytic-abundance quotient (CAQ) of reactions within a pathway that defines the condition for maximal efficiency. By integrating reaction thermodynamics, enzyme kinetics, transcriptomic, and proteomic data, we compared enzyme allocation in glycolysis and the TCA cycle with this K-CAQ relationship across evolutionarily distant species, and showed that deviation from it can be explained by a trade-off between maximizing flux efficiency and concentrating flux control. Moreover, the drive to optimize glycolytic efficiency is strengthened under oncogenic signaling and a limited cellular budget for glycolytic enzymes. These findings establish a principle of Pareto optimality governing enzyme allocation in metabolic pathways and reveal key determinants of efficiency optimality in glycolysis.