Thermodynamic Cost-Controllability Tradeoff in Metabolic Currency Coupling

Cellular metabolism is globally regulated by various currency metabolites such as ATP, GTP, and NAD(P)H. These metabolites cycle between charged (high-energy) and uncharged (low-energy) states to mediate energy transfer. While distinct currency metabolites are associated with different metabolic functions, their charged and uncharged forms are generally interconverted through biochemical reactions such as ATP + GDP ⇌ ADP + GTP and NADP + + NADH ⇌ NADPH + NAD + . Thus, their energetic states are generally coupled and influence each other, which would hinder the independent regulation of different currency metabolites. Despite extensive knowledge of the molecular biology of individual currency metabolites, it remains poorly understood how the coordination of various coupled currency metabolites shapes metabolic regulation, efficiency, and ultimately the evolution of organisms. Here, we present a minimal theoretical model of metabolic currency coupling and reveal a fundamental tradeoff relationship between metabolic controllability and thermodynamic cost: increasing the capacity to independently regulate multiple currency metabolites generally requires comparable abundances of those metabolites, which in turn incurs a higher entropy production rate. The tradeoff suggests that in complex environments, organisms evolutionarily favor comparably sized currency-metabolite pools to enhance metabolic controllability at the expense of a higher thermodynamic cost; conversely, in simple environments, organisms are expected to evolve more imbalanced currency pools to reduce heat dissipation. These considerations also offer a hypothesis regarding evolutionary trends in nucleotide-pool balance and genomic GC content.