Abstract
Genome-scale models of metabolism (GEM) are used to study how metabolism varies in different physiological conditions. However, the great number of reactions involved in GEM makes it difficult to understand these variations. In order to have a more understandable tool, we developed a reduced metabolic model of central carbon and nitrogen metabolism, C2M2N with 77 reactions, 54 internal metabolites, and 3 compartments, taking into account the actual stoichiometry of the reactions, including the stoichiometric role of the cofactors and the irreversibility of some reactions. In order to model oxidative phosphorylation (OXPHOS) functioning, the proton gradient through the inner mitochondrial membrane is represented by two pseudometabolites DPH (∆pH) and DPSI (∆ψ). To illustrate the interest of such a reduced and quantitative model of metabolism in mammalian cells, we used flux balance analysis (FBA) to study all the possible fates of glutamine in metabolism. Our analysis shows that glutamine can supply carbon sources for cell energy production and can be used as carbon and nitrogen sources to synthesize essential metabolites. Finally, we studied the interplay between glucose and glutamine for the formation of cell biomass according to ammonia microenvironment. We then propose a quantitative analysis of the Warburg effect.
Highlights
Genome-scale models of metabolism (GEM) greatly help to understand how metabolism varies in different physiological conditions, in different environments, in case of enzyme deficiencies, and in interaction with other metabolisms
One molecule of malate generates pyruvate and acetyl-CoA, which will condense with the OAA derived from the remaining molecule of malate, to generate citrate and a canonical tricarboxylic acid (TCA) cycle continue in the usual direction with a flux equal to 1
We developed a core metabolic model of central carbon and nitrogen metabolism, C2M2N, with a limited number of reactions (77) and of metabolites (54 internal metabolites) to explore the potential of glutamine to supplant glucose in metabolic syntheses, energy and biomass production
Summary
Genome-scale models of metabolism (GEM) greatly help to understand how metabolism varies in different physiological conditions, in different environments, in case of enzyme deficiencies, and in interaction with other metabolisms. In C2M2N, the model of OXPHOS functioning is based on a proton gradient through the inner mitochondrial membrane, represented here by two pseudometabolites DPH (∆pH) and DPSI (∆ψ). Using flux balance analysis (FBA), we systematically studied and quantitatively discussed all the possible fates of glutamine in central carbon metabolism and demonstrated that glutamine can sustain cell energy production and be used as a carbon and nitrogen source to synthesize essential metabolites, contributing to cell proliferation. In a more general approach, we used C2M2N to follow how glucose and glutamine together share energy metabolism and anabolism in different physiological or pathological conditions (proliferating cells, hypoxia). We demonstrated the interest of a core stoichiometric model such as C2M2N in quantitatively tracing the origin of the carbon and nitrogen atoms in the different syntheses and in specifying the respective role of glutamine and glucose in energy metabolism. We gave a quantitative account of Warburg effect evidencing the main challenge of proliferating cells, i.e., energy production while maintaining nicotinamide adenine dinucleotide (NAD/NADH) balance
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