TY - JOUR
T1 - Whole-cell modeling in yeast predicts compartment-specific proteome constraints that drive metabolic strategies
AU - Elsemman, Ibrahim E.
AU - Rodriguez Prado, Angelica
AU - Grigaitis, Pranas
AU - Garcia Albornoz, Manuel
AU - Harman, Victoria
AU - Holman, Stephen W.
AU - van Heerden, Johan
AU - Bruggeman, Frank J.
AU - Bisschops, Mark M.M.
AU - Sonnenschein, Nikolaus
AU - Hubbard, Simon
AU - Beynon, Rob
AU - Daran-Lapujade, Pascale
AU - Nielsen, Jens
AU - Teusink, Bas
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-022-28467-6
DO - 10.1038/s41467-022-28467-6
M3 - Journal article
C2 - 35145105
AN - SCOPUS:85124447176
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 801
ER -