Forces, Fluxes and the Control of Microbial Growth and Metabolism: The Twelfth Fleming Lecture

This Fleming Lecture by Douglas B. Kell examines the thermodynamic and metabolic principles controlling microbial growth and metabolism. The author presents microbial cells as non-equilibrium thermodynamic energy converters that couple catabolic (energy-generating) and anabolic (biosynthetic) processes through the adenine nucleotide system. He demonstrates that bacterial growth efficiency is typically low, around 25% at maximum, because organisms have evolved to maximize metabolic flux and growth rate rather than thermodynamic efficiency. The lecture explores whether growth is limited more by catabolism or anabolism, introducing metabolic control analysis—a quantitative framework using flux-control coefficients to determine which enzymes regulate metabolic pathways. A key finding challenges the pool model of metabolic intermediates, suggesting that some energy-coupling systems, particularly electron-transport-linked phosphorylation, may involve channeled rather than delocalized intermediates. The author argues that understanding microbial growth control requires rigorous mathematical analysis of steady-state metabolic systems and examination of how forces and fluxes interact within cellular energy-conversion pathways.

Key findings

• Bacterial growth exhibits low thermodynamic efficiency (~25%) because organisms have evolved to maximize metabolic flux rate rather than energy yield, using only a fraction of generated free energy for biosynthesis.
• Metabolic control analysis reveals that growth rate limitation cannot be attributed simply to either catabolism or anabolism alone, but results from distributed control across multiple enzymatic steps.
• Evidence from inhibitor titration experiments suggests that electron-transport-linked phosphorylation may involve channeled energy transfer rather than pool-based (delocalized) intermediates, challenging Mitchell's chemiosmotic coupling hypothesis.
• The flux-control summation theorem provides a quantitative framework to assess which enzymes control metabolic fluxes under specific conditions, applicable to understanding and optimizing microbial fermentations.