Metabolism is at the core of cellular functions as it provides energy and building blocks required for cellular maintenance and growth; there is therefore much interest in the driving forces that shape metabolic adaptations. In bacteria, constraints on cellular resources explain allocation of proteins to different cellular processes. In eukaryotes, however, metabolism is distributed into several different compartments. Thus it is unclear which constraints shape cellular metabolism. Here we integrated metabolic fluxes and proteomics data with a genome-scale model of budding yeast Saccharomyces cerevisiae, enhanced with detailed, growth rate-dependent, description of protein turnover and associated, compartment-specific, proteome constraints. We find that the Crabtree effect, i.e. the onset of alcoholic fermentation (analogous to the Warburg effect in cancer) is governed by mitochondrial or cytosolic constraints, depending on nutrient availability and quality. These effects are reflected in predictions of condition- and compartment-specific proteome composition, which are in agreement with quantitative proteomics measurements. Our modeling approach provides a powerful platform to study multiple scenarios of compartment-specific yeast metabolism at genome-scale in a fine-grained manner.
COMPARTMENT-SPECIFIC PROTEOME CONSTRAINTS DRIVE CHANGES IN YEAST METABOLISM
Pranas Grigaitis1, Ibrahim El-Semman2, 7, Angelica Rodrigues Prado1, 3, Manuel Garcia Albornoz4, Victoria Harman5, Stephen Holman5, Johan van Heerden1, Simon Hubbard6, Rob Beynon5, Frank J. Bruggeman1, Pascale Daran-Lapujade3, Nikolaus Sonnenschein2, Jens Nielsen2, 6, Bas Teusink1
1 Systems Biology Lab, Amsterdam Institute of Molecular and Life Sciences, VU Amsterdam, The Netherlands
2 Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK2800 Lyngby, Denmark
3 Department of Industrial Microbiology, Technical University Delft, Delft, The Netherlands
4 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
5 Department of Biochemistry, Institute of Integrative Biology, Biosciences Building, University of Liverpool, Liverpool, United Kingdom
6 Department of Biology and Biological Engineering, Chalmers University of Technology, SE41296 Gothenburg, Sweden
7 Department of Mathematics, Faculty of Science, Assiut University, Assiut, Egypt (On leave)