A Multiphase Multiobjective Dynamic Genome-Scale Model Shows Different Redox Balancing among Yeast Species of the Saccharomyces Genus in Fermentation

Yeasts constitute over 1,500 species with great potential for biotechnology. Still, the yeast Saccharomyces cerevisiae dominates industrial applications, and many alternative physiological capabilities of lesser-known yeasts are not being fully exploited. While comparative genomics receives substantial attention, little is known about yeasts' metabolic specificity in batch cultures. Here, we propose a multiphase multiobjective dynamic genome-scale model of yeast batch cultures that describes the uptake of carbon and nitrogen sources and the production of primary and secondary metabolites. The model integrates a specific metabolic reconstruction, based on the consensus Yeast8, and a kinetic model describing the time-varying culture environment. In addition, we proposed a multiphase multiobjective flux balance analysis to compute the dynamics of intracellular fluxes. We then compared the metabolism of S. cerevisiae and Saccharomyces uvarum strains in a rich medium fermentation. The model successfully explained the experimental data and brought novel insights into how cryotolerant strains achieve redox balance. The proposed model (along with the corresponding code) provides a comprehensive picture of the main steps occurring inside the cell during batch cultures and offers a systematic approach to prospect or metabolically engineering novel yeast cell factories. Nonconventional yeast species hold the promise to provide novel metabolic routes to produce industrially relevant compounds and tolerate specific stressors, such as cold temperatures. This work validated the first multiphase multiobjective genome-scale dynamic model to describe carbon and nitrogen metabolism throughout batch fermentation. To test and illustrate its performance, we considered the comparative metabolism of three yeast strains of the genus in rich medium fermentation. The study revealed that cryotolerant species might use the γ-aminobutyric acid (GABA) shunt and the production of reducing equivalents as alternative routes to achieve redox balance, a novel biological insight worth being explored further. The proposed model (along with the provided code) can be applied to a wide range of batch processes started with different yeast species and media, offering a systematic and rational approach to prospect nonconventional yeast species metabolism and engineering novel cell factories.