Abstract
Energy metabolism is crucial for all living cells, especially
during fast growth or stress scenarios. Many cancer and
activated immune cells (Warburg effect) or yeasts (Crabtree
effect) mostly rely on aerobic glucose fermentation leading to
lactate or ethanol, respectively, to generate ATP. In recent
years, several mathematical models have been proposed to explain
the Warburg effect on theoretical grounds. Besides glucose,
glutamine is a very important substrate for eukaryotic cells-not
only for biosynthesis, but also for energy metabolism. Here, we
present a minimal constraint-based stoichiometric model for
explaining both the classical Warburg effect and the
experimentally observed respirofermentation of glutamine
(WarburQ effect). We consider glucose and glutamine respiration
as well as the respective fermentation pathways. Our resource
allocation model calculates the ATP production rate, taking into
account enzyme masses and, therefore, pathway costs. While our
calculation predicts glucose fermentation to be a superior
energy-generating pathway in human cells, different enzyme
characteristics in yeasts reduce this advantage, in some cases
to such an extent that glucose respiration is preferred. The
latter is observed for the fungal pathogen Candida albicans,
which is a known Crabtree-negative yeast. Further, optimization
results show that glutamine is a valuable energy source and
important substrate under glucose limitation, in addition to its
role as a carbon and nitrogen source of biomass in eukaryotic
cells. In conclusion, our model provides insights that glutamine
is an underestimated fuel for eukaryotic cells during fast
growth and infection scenarios and explains well the observed
parallel respirofermentation of glucose and glutamine in several
cell types.
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