Biochemical principles enabling metabolic cooperativity and phenotypic heterogeneity at the single cell level
Review article, 2018

All biosynthetically active cells release metabolites, in part due to membrane leakage and cell lysis, but also in part due to overflow metabolism and ATP-dependent membrane export. At the same time, cells are adapted to sense and take up extracellular nutrients when available, to minimize the number of biochemical reactions that have to operate within a cell in parallel, and ultimately, to gain metabolic efficiency and biomass. Within colonies, biofilms or tissues, the co-occurrence of metabolite export and import enables the sharing of metabolites as well as metabolic specialization of single cells. In this review we discuss emerging biochemical concepts that give reasoning for why cells overproduce and release metabolites, and how these form the foundations for cooperative metabolite exchange activity between cells. We place particular emphasis on discussing the role of overflow metabolism in cells that exhibit either the Warburg or Crabtree effect. Furthermore, we discuss the profound physiological changes that cells undergo when their metabolism switches from metabolite synthesis to uptake, providing an explanation why metabolic specialization results in non-genotypic heterogeneity at the single cell level.

Crabtree effect

Metabolite exchange

Overflow metabolism

Metabolite sensing


Warburg effect

Phenotypic heterogeneity


Kate Campbell

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Lucia Herrera-Dominguez

The Francis Crick Institute

Clara Correia-Melo

University of Cambridge

The Francis Crick Institute

Aleksej Zelezniak

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Science for Life Laboratory (SciLifeLab)

The Francis Crick Institute

M. Ralser

The Francis Crick Institute

University of Cambridge

Current Opinion in Systems Biology

24523100 (eISSN)

Vol. 8 97-108

Subject Categories

Cell Biology

Cell and Molecular Biology

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)



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