TY - JOUR
T1 - The common message of constraint-based optimization approaches
T2 - Overflow Metabolism Is Caused by Two Growth-Limiting Constraints
AU - De Groot, Daan
AU - Lischke, Julia
AU - Muolo, Riccardo
AU - Planqué, Robert
AU - Bruggeman, Frank J.
AU - Teusink, Bas
N1 - Funding Information:
DHdG and BT acknowledge NWO VICI grant 865.14.005, JL thanks EraCoBiotech grant YogurtDesign (NWO Grant 053.80.733) and RM acknowledges ITN SynCrop (Grant agreement no 764591) for financial support.
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
KW - Elementary flux modes
KW - Elementary growth modes
KW - Genome-scale modeling
KW - Growth rate maximization
KW - Metabolism and expression
KW - Overflow metabolism
UR - http://www.scopus.com/inward/record.url?scp=85075375160&partnerID=8YFLogxK
U2 - 10.1007/s00018-019-03380-2
DO - 10.1007/s00018-019-03380-2
M3 - Article
SN - 1420-682X
VL - 77
SP - 441
EP - 453
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 3
ER -