4. Discussion
Our results address critical questions in metabolism, such as changes in
metabolic fluxes due to pH constraint, what shifts the metabolic
pathways, and what induces cells to adjust the way they perform their
metabolism, as illustrated by the shift in metabolism from pH 7 to 5.
Our strategy proposes optimizing growth under the constraint of pH as
the central principle shaping metabolism. The pH changes contribute to a
redirection of metabolic fluxes (for example, shift to TCA cycle under
acidic conditions) as the exchange rates of proton increase and cells
aim to optimize their growth. This finding suggests that the developed
charge-balanced models are capable of revealing the physiological
properties of the cells and that the models are a more suitable platform
for addressing the challenges of using these cells in bio-based
production.
Our work also shows that a limit of pH in modeling could constrain
cellular metabolism. This constraint is undoubtedly a universal and
physical metabolism restriction that can be applied not only in
eukaryotes (yeast) but also in prokaryotes (E. coli , Z.
mobilis ). Besides, our principle of metabolic flux prediction provides
an advantage over conventional FBA-based techniques, since it
systematically investigates metabolism in order to perform better and
more effectively in metabolic engineering approaches. The findings draw
on previous research in S. cerevisiae and other microorganisms,
which is aligned with our results that substrate concentration changes
are a significant contributor to overall flux distribution
changes(Daran-Lapujade et al., 2004; Gerosa et al., 2015; Valgepea,
Adamberg, Seiman, & Vilu, 2013). Meanwhile, despite the value ofS. cerevisiae as an industrial microorganism, our observations
into its regulatory metabolic flux at various pH levels may be of
substantial benefit in systems metabolic engineering. Therefore, using
genome-scale metabolic models to evaluate pH effect can provide
comprehensive solutions to improve biofuels, biomedicine, and bio-based
production, especially reduced products such as ethanol.