The common message of constraint-based optimization approaches: overflow metabolism is caused by two growth-limiting constraints

Daan H. de Groot*, Julia Lischke, Riccardo Muolo, Robert Planqué, Frank J. Bruggeman, Bas Teusink

*Corresponding author for this work

Research output: Contribution to JournalReview articleAcademicpeer-review


Living cells can express different metabolic pathways that support growth. The criteria that determine which pathways are selected in which environment remain unclear. One recurrent selection is overflow metabolism: the simultaneous usage of an ATP-efficient and -inefficient pathway, shown for example in Escherichia coli, Saccharomyces cerevisiae and cancer cells. Many models, based on different assumptions, can reproduce this observation. Therefore, they provide no conclusive evidence which mechanism is causing overflow metabolism. We compare the mathematical structure of these models. Although ranging from flux balance analyses to self-fabricating metabolism and expression models, we can rewrite all models into one standard form. We conclude that all models predict overflow metabolism when two, model-specific, growth-limiting constraints are hit. This is consistent with recent theory. Thus, identifying these two constraints is essential for understanding overflow metabolism. We list all imposed constraints by these models, so that they can hopefully be tested in future experiments.

Original languageEnglish
Pages (from-to)441-453
Number of pages13
JournalCellular and Molecular Life Sciences
Issue number3
Early online date22 Nov 2019
Publication statusPublished - 1 Feb 2020



  • Elementary flux modes
  • Elementary growth modes
  • Genome-scale modeling
  • Growth rate maximization
  • Metabolism and expression
  • Overflow metabolism

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