Using Kinetic Modelling to Infer Adaptations in Saccharomyces cerevisiae Carbohydrate Storage Metabolism to Dynamic Substrate Conditions

David Lao-Martil*, Koen J.A. Verhagen, Ana H. Valdeira Caetano, Ilse H. Pardijs, Natal A.W. van Riel, S. Aljoscha Wahl

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

1 Citation (Scopus)
64 Downloads (Pure)

Abstract

Microbial metabolism is strongly dependent on the environmental conditions. While these can be well controlled under laboratory conditions, large-scale bioreactors are characterized by inhomogeneities and consequently dynamic conditions for the organisms. How Saccharomyces cerevisiae response to frequent perturbations in industrial bioreactors is still not understood mechanistically. To study the adjustments to prolonged dynamic conditions, we used published repeated substrate perturbation regime experimental data, extended it with proteomic measurements and used both for modelling approaches. Multiple types of data were combined; including quantitative metabolome, 13C enrichment and flux quantification data. Kinetic metabolic modelling was applied to study the relevant intracellular metabolic response dynamics. An existing model of yeast central carbon metabolism was extended, and different subsets of enzymatic kinetic constants were estimated. A novel parameter estimation pipeline based on combinatorial enzyme selection supplemented by regularization was developed to identify and predict the minimum enzyme and parameter adjustments from steady-state to dynamic substrate conditions. This approach predicted proteomic changes in hexose transport and phosphorylation reactions, which were additionally confirmed by proteome measurements. Nevertheless, the modelling also hints at a yet unknown kinetic or regulation phenomenon. Some intracellular fluxes could not be reproduced by mechanistic rate laws, including hexose transport and intracellular trehalase activity during substrate perturbation cycles.

Original languageEnglish
Article number88
Number of pages20
JournalMetabolites
Volume13
Issue number1
DOIs
Publication statusPublished - 2023

Keywords

  • adaptation
  • carbon storage metabolism
  • glucose transport
  • kinetic modeling
  • parameter estimation
  • repeated substrate perturbation regime
  • Saccharomyces cerevisiae

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