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Cell Mol Life Sci. 2019 Nov 22. doi: 10.1007/s00018-019-03380-2. [Epub ahead of print]

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

Author information

1
Systems Bioinformatics, AIMMS, Vrije Universiteit Amsterdam, 1081HZ, Amsterdam, The Netherlands. d.h.de.groot@vu.nl.
2
Systems Bioinformatics, AIMMS, Vrije Universiteit Amsterdam, 1081HZ, Amsterdam, The Netherlands.
3
Department of Mathematics, Vrije Universiteit Amsterdam, 1081HV, Amsterdam, The Netherlands.

Abstract

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.

KEYWORDS:

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

PMID:
31758233
DOI:
10.1007/s00018-019-03380-2

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