Whole-cell modeling in yeast predicts compartment-specific proteome constraints that drive metabolic strategies
Journal article, 2022
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.
Author
Ibrahim El-Semman
Technical University of Denmark (DTU)
Assiut University
Angelica Rodriguez Prado
Vrije Universiteit Amsterdam
Delft University of Technology
Pranas Grigaitis
Vrije Universiteit Amsterdam
Manuel Garcia
University of Manchester
Victoria Harman
University of Liverpool
Stephen W. Holman
University of Liverpool
Johan van Heerden
Vrije Universiteit Amsterdam
Frank J. Bruggeman
Vrije Universiteit Amsterdam
Mark Bisschops
Delft University of Technology
N. Sonnenschein
Technical University of Denmark (DTU)
Simon Hubbard
University of Manchester
Rob Beynon
University of Liverpool
P. Daran-Lapujade
Delft University of Technology
Jens B Nielsen
Technical University of Denmark (DTU)
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
B. Teusink
Vrije Universiteit Amsterdam
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 13 1 801Subject Categories
Cell Biology
Biochemistry and Molecular Biology
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
DOI
10.1038/s41467-022-28467-6
PubMed
35145105