Integrative Thermodynamics Strategies in Microbial Metabolism

Microbial metabolism is intricately governed by thermodynamic constraints that dictate energetic efficiency, growth dynamics, and metabolic pathway selection. Previous research has primarily examined these principles under carbon-limited conditions, demonstrating how microbes optimize their proteomic resources to balance metabolic efficiency and growth rates. This study extends this thermodynamic framework to explore microbial metabolism under various non-carbon nutrient limitations (e.g., nitrogen, phosphorus, sulfur). By integrating literature data from a range of species it is shown that growth under anabolic nutrient limitations consistently results in more negative Gibbs free energy (ΔG) values for the Net Catabolic Reaction (NCR), when normalized per unit of biomass formed, compared to carbon-limited scenarios. The findings suggest three, potentially complementary hypotheses: (1) Proteome Allocation Hypothesis: microbes favor faster enzymes to reduce proteome fraction used for catabolism, thus freeing proteome resources for additional nutrient transporters; (2) Coupled Transport Contribution Hypothesis: The more negative ΔG of the NCR may in part stem from the increased reliance on ATP-coupled or energetically driven transport mechanisms for nutrient uptake under limitation; (3) Bioenergetic Efficiency Hypothesis: microbes prefer pathways with more negative ΔG to enhance cellular energy status, such as membrane potentials or ATP/ADP ratio, to support nutrient uptake under anabolic limitations. This integrative thermodynamic analysis broadens the understanding of microbial adaptation strategies and provides valuable insights for biotechnological applications in metabolic engineering and fermentation process optimization.