The pcYeast7.6 model and files, required to reproduce the figures, provided in the publication "Whole-cell modeling in yeast predicts compartment-specific proteome constraints that drive metabolic strategies", accepted in Nat Commun. The Zenodo upload was created by Pranas Grigaitis, p.grigaitis [at] vu.nl. 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 optimization, providing a framework to understand metabolic adaptation in eukaryal cells.

This work was supported by NWO (NWO ERA-IB-2, project No 053.80.722 to BT and PDL), ERA-IB 4207-00002B DSForsk to JN, and Biotechnology and Biological Sciences Research Council (BB/M025748/1 to SH, BB/M025756/1 to RB). PG and BT also acknowledge support by Marie Sk��odowska-Curie Actions ITN "SynCrop" (grant agreement No 764591). We thank SURFsara for the HPC resources through access to the Lisa Compute Cluster.