Abstract
AbstractRecent experimental evidence indicates that some cancer cells have an alternative glycolysis pathway with net zero ATP production, implying that upregulation of glycolysis in these cells may not be related to the generation of ATP. Here we use a genome-scale model of human cell metabolism to investigate the potential metabolic alterations in cells using net zero ATP glycolysis. We uncover a novel pathway for ATP generation that involves reactions from the serine biosynthesis and one-carbon metabolism pathways. This pathway has a predicted two-fold higher flux rate in cells using net zero ATP glycolysis than those using standard glycolysis and generates twice as much ATP with significantly lower rate of lactate- but higher rate of alanine secretion. Thus, in cells using the standard- or the net zero ATP glycolysis pathways a significant portion of the glycolysis flux is always associated with ATP generation, and the ratio between the flux rates of the two pathways determines the rate of ATP generation and lactate and alanine secretion during glycolysis.
Highlights
Oxidative phosphorylation (OxPhos) in the mitochondria is the major pathway for ATP generation in normal cells under normal oxygen conditions, generating 32 mole of ATP per mole of glucose [1]
An alternative hypothesis suggests that the increased rate of glycolysis in rapidly proliferating cells is present to support the increased demand for precursor metabolites by anabolic processes involved in cell growth and proliferation [24]
We have recapitulated this result here, using the alternative glycolysis pathway with net zero ATP production, providing in silico evidence that the demand for precursor metabolites can be satisfied without upregulation of the alternative glycolysis pathway (Fig. 2)
Summary
Oxidative phosphorylation (OxPhos) in the mitochondria is the major pathway for ATP generation in normal cells under normal oxygen conditions (normoxia), generating 32 mole of ATP per mole of glucose [1]. Despite the importance of OxPhos and aerobic glycolysis in ATP generation, more recent empirical evidence indicates that some cancer cells utilize an alternative glycolysis pathway with net zero ATP generation [12]. This striking observation implies a physiological role for aerobic glycolysis other than ATP generation. We have shown previously that this maximum is achieved at physiological conditions and that it results in a metabolic switch involving an upregulation of glycolysis and lactate excretion [14,15] All these results were obtained making use of the standard glycolysis pathway, with a yield of 2 moles of ATP per mole of glucose
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