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An Evolutionary Systems Biology View on Metabolic System Structure and Dynamics


Cellular metabolism consists of many interconnected reactions that present feedbacks through cyclic reaction motifs and through metabolite regulation of enzyme kinetics. In addition, metabolism is interlinked with gene regulation and other cellular, energy-driven processes such as division and motility. While many important insights have been gained on metabolism in the last decades, we are still far from a complete, predictive understanding of it. This is reflected in our current, limited ability to pinpoint the drivers of metabolic system dynamics and devising ways to engineer it.

In this review paper, we argue that the study of metabolism through the lens of evolutionary biology can provide further insights into its structure and dynamics. By structure, we mean the composing reactions of a metabolic system, and how these reactions are connected with each other through shared metabolites, while by dynamics, we mean the temporal behaviour and responses of the resulting metabolic system. Following an introductory section, we summarise the key findings on the structure and dynamics of cellular metabolism within an evolutionary systems perspective in Sects. 2 and 3. In doing so, we highlight two key ways of thinking about metabolic systems, one based on considering metabolism optimised for biomass production, and another one based on considering metabolism as a self-regulating emergent system for maintaining nonequilibrium metabolic fluxes. From this second consideration, we then expand to discuss the possible biophysical drivers that could have played a key role in shaping metabolic systems in Sect. 4. Finally, in Sect. 5, we call for an evolutionary perspective on metabolism that takes into account both of the above considerations. We conclude by highlighting key areas of future research where this combined view can provide valuable insights.


  • TCA cycle
  • Allosteric regulation
  • Biomass production
  • Biophysical constraints
  • Biophysical drivers
  • Bioproduction
  • Biotechnological applications
  • Bistability
  • Carbon preference
  • Catabolic hierarchy
  • Catabolic pathway switching
  • Catabolic pathways
  • Causative mechanisms
  • Cell cycle oscillations
  • Cell division
  • Cell metabolism
  • Cell physiology
  • Cellular behaviours
  • Cellular metabolism
  • Chemical gradients
  • Competitive-exclusion principle
  • Contre-effet Pasteur
  • Warburg effect
  • Crabtree effect
  • Cross-feeding
  • Curse of dimensionality
  • Cyclic reaction schemes
  • Cyclic reaction system
  • Degree distribution
  • Dynamical process
  • Ecology-evolutionary feedbacks
  • Elementary flux modes
  • Energy production
  • Energy spilling
  • Engineering perspective
  • Entropy maximisation
  • Environmental fluctuations
  • Enzymatic reactions
  • Enzyme cost minimisation
  • Enzyme function
  • Enzyme investment
  • Evolutionary biology
  • Evolutionary constraints
  • Evolutionary drivers
  • Evolutionary systems perspective
  • Explanatory and predictive indicators
  • Extracellular entropic gradients
  • Fermentation
  • Flux balance analysis
  • Flux rate constraints
  • Flux-sensing
  • Functionally redundant pathways
  • Gene expression
  • Gene regulation
  • Glycolysis
  • Homeostasis
  • Hubs
  • In silico evolution
  • Interlinked reaction cycles
  • Kinetic parameters
  • Membrane potential
  • Metabolic adaptation
  • Metabolic evolution
  • Metabolic fluxes
  • Metabolic gradients
  • Metabolic overflows
  • Metabolic regulation
  • Metabolic shifts
  • Metabolic system
  • Metabolic system dynamics
  • Metabolic system structure
  • Metabolite regulation
  • Modularity
  • Modules
  • Motility
  • Multi-stability
  • Network analyses
  • Network modularity
  • Network motifs
  • Network representation
  • Non-adaptive explanations
  • Non-adaptive mechanisms
  • Nonequilibrium thermodynamics
  • Nonlinear dynamics
  • Oscillation
  • Oscillations
  • Over-represented motifs
  • Pathway switching
  • Pathways
  • Perturbations
  • Phase separation
  • Phylogenetic distributions
  • Physico-chemical constraints
  • Predictive understanding
  • Preferential attachment
  • Promiscuous functions
  • Reaction maps
  • Reaction motif
  • Redox reactions
  • Regulatory system
  • Resource balance analysis
  • Respiration
  • Robustness
  • Scale-free connectivity distribution
  • Selectable traits
  • Self-forming coacervates
  • Self-regulating emergent system
  • Self-replication
  • Single-cell analyses
  • Single-cell measurements
  • Spatially organised systems
  • Steady state fluxes
  • Stoichiometric modelling
  • Supply-demand
  • Sustained viability
  • Temporal behaviour
  • Thermodynamic constraints
  • Thermodynamic equilibrium
  • Thermodynamic inhibition
  • Thermodynamic regulation
  • Thermodynamics
  • Threshold dynamics
  • Toy metabolic models
  • Transcription factor
  • Ultrasensitivity

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We thank Marco Polin, Munehiro Asally, and Christian Zerfass for comments on an earlier version of this manuscript.

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Correspondence to Orkun S. Soyer .

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Johnson, C., Delattre, H., Hayes, C., Soyer, O.S. (2021). An Evolutionary Systems Biology View on Metabolic System Structure and Dynamics. In: Crombach, A. (eds) Evolutionary Systems Biology. Springer, Cham.

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