Whole-cell modeling in yeast predicts compartment-specific proteome constraints that drive metabolic strategies

Ibrahim E. Elsemman, Angelica Rodriguez Prado, Pranas Grigaitis, Manuel Garcia Albornoz, Victoria Harman, Stephen W. Holman, Johan Heerden, Frank J. Bruggeman, Mark M. M. Bisschops, Nikolaus Sonnenschein, Simon Hubbard, Rob Beynon, Pascale Daran-Lapujade, Jens Nielsen () and Bas Teusink ()
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Ibrahim E. Elsemman: Technical University of Denmark
Angelica Rodriguez Prado: Vrije Universiteit Amsterdam
Pranas Grigaitis: Vrije Universiteit Amsterdam
Manuel Garcia Albornoz: University of Manchester
Victoria Harman: University of Liverpool
Stephen W. Holman: University of Liverpool
Johan Heerden: Vrije Universiteit Amsterdam
Frank J. Bruggeman: Vrije Universiteit Amsterdam
Mark M. M. Bisschops: Technical University Delft
Nikolaus Sonnenschein: Technical University of Denmark
Simon Hubbard: University of Manchester
Rob Beynon: University of Liverpool
Pascale Daran-Lapujade: Technical University Delft
Jens Nielsen: Technical University of Denmark
Bas Teusink: Vrije Universiteit Amsterdam

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract When conditions change, unicellular organisms rewire their metabolism to sustain cell maintenance and cellular growth. Such rewiring may be understood as resource re-allocation under cellular constraints. Eukaryal cells contain metabolically active organelles such as mitochondria, competing for cytosolic space and resources, and the nature of the relevant cellular constraints remain to be determined for such cells. Here, we present a comprehensive metabolic model of the yeast cell, based on its full metabolic reaction network extended with protein synthesis and degradation reactions. The model predicts metabolic fluxes and corresponding protein expression by constraining compartment-specific protein pools and maximising growth rate. Comparing model predictions with quantitative experimental data suggests that under glucose limitation, a mitochondrial constraint limits growth at the onset of ethanol formation—known as the Crabtree effect. Under sugar excess, however, a constraint on total cytosolic volume dictates overflow metabolism. Our comprehensive model thus identifies condition-dependent and compartment-specific constraints that can explain metabolic strategies and protein expression profiles from growth rate optimisation, providing a framework to understand metabolic adaptation in eukaryal cells.

Date: 2022
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DOI: 10.1038/s41467-022-28467-6

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