Impact of limited solvent capacity on metabolic rate, enzyme activities, and metabolite concentrations of S. cerevisiae glycolysis

The cell's cytoplasm is crowded by its various molecular components, resulting in a limited solvent capacity for the allocation of new proteins, thus constraining various cellular processes such as metabolism. Here we study the impact of the limited solvent capacity constraint on the metabolic rate, enzyme activities, and metabolite concentrations using a computational model of Saccharomyces cerevisiae glycolysis as a case study. We show that given the limited solvent capacity constraint, the optimal enzyme activities and the metabolite concentrations necessary to achieve a maximum rate of glycolysis are in agreement with their experimentally measured values. Furthermore, the predicted maximum glycolytic rate determined by the solvent capacity constraint is close to that measured in vivo. These results indicate that the limited solvent capacity is a relevant constraint acting on S. cerevisiae at physiological growth conditions, and that a full kinetic model together with the limited solvent capacity constraint can be used to predict both metabolite concentrations and enzyme activities in vivo. © 2008 Vazquez et al

Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology

Aerobic glycolysis is a seemingly wasteful mode of ATP production that is seen both in rapidly proliferating mammalian cells and highly active contracting muscles, but whether there is a common origin for its presence in these widely different systems is unknown. To study this issue, here we develop a model of human central metabolism that incorporates a solvent capacity constraint of metabolic enzymes and mitochondria, accounting for their occupied volume densities, while assuming glucose and/or fatty acid utilization. The model demonstrates that activation of aerobic glycolysis is favored above a threshold metabolic rate in both rapidly proliferating cells and heavily contracting muscles, because it provides higher ATP yield per volume density than mitochondrial oxidative phosphorylation. In the case of muscle physiology, the model also predicts that before the lactate switch, fatty acid oxidation increases, reaches a maximum, and then decreases to zero with concomitant increase in glucose utilization, in agreement with the empirical evidence. These results are further corroborated by a larger scale model, including biosynthesis of major cell biomass components. The larger scale model also predicts that in proliferating cells the lactate switch is accompanied by activation of glutaminolysis, another distinctive feature of the Warburg effect. In conclusion, intracellular molecular crowding is a fundamental constraint for cell metabolism in both rapidly proliferating- and non-proliferating cells with high metabolic demand. Addition of this constraint to metabolic flux balance models can explain several observations of mammalian cell metabolism under steady state conditions

Serine biosynthesis with one carbon catabolism represents a novel pathway for ATP generation in cells using alternative glycolysis with zero net ATP production

Recent 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

Serine biosynthesis with one carbon catabolism represents a novel pathway for ATP generation in cells using alternative glycolysis with zero net ATP production

Recent 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

Serine Biosynthesis with One Carbon Catabolism and the Glycine Cleavage System Represents a Novel Pathway for ATP Generation

Previous 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 serine biosynthesis, one-carbon metabolism and the glycine cleavage system, and show that the pathway is transcriptionally upregulated in an inducible murine model of Myc-driven liver tumorigenesis. 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

Impact of limited solvent capacity on metabolic rate, enzyme activities, and metabolite concentrations of S. cerevisiae glycolysis.

The cell's cytoplasm is crowded by its various molecular components, resulting in a limited solvent capacity for the allocation of new proteins, thus constraining various cellular processes such as metabolism. Here we study the impact of the limited solvent capacity constraint on the metabolic rate, enzyme activities, and metabolite concentrations using a computational model of Saccharomyces cerevisiae glycolysis as a case study. We show that given the limited solvent capacity constraint, the optimal enzyme activities and the metabolite concentrations necessary to achieve a maximum rate of glycolysis are in agreement with their experimentally measured values. Furthermore, the predicted maximum glycolytic rate determined by the solvent capacity constraint is close to that measured in vivo. These results indicate that the limited solvent capacity is a relevant constraint acting on S. cerevisiae at physiological growth conditions, and that a full kinetic model together with the limited solvent capacity constraint can be used to predict both metabolite concentrations and enzyme activities in vivo

Métabolisme énergétique cardiaque fœtal dans un modèle de restriction de croissance intra-utérine chez le rat

Une diète faible en sodium donnée à des rates lors de la dernière semaine de gestation induit une diminution de l’expansion volumique, du diamètre des artères utérines et du poids des placentas comparativement à des rates témoins. Ces perturbations suggèrent une diminution de la perfusion placentaire affectant l’apport foetal en nutriments. Les ratons naissent avec une restriction de croissance intra-utérine (RCIU). Chez le foetus, le substrat énergétique cardiaque principal est le glucose via la glycolyse. À la naissance, la source principale d’énergie est l’utilisation des acides gras par la β-oxydation. Nous émettons l’hypothèse que dans ce modèle de RCIU, le coeur foetal répond à la diminution d’apport nutritionnel due à une atteinte maternelle en adaptant son métabolisme énergétique cardiaque à la baisse. Les rates gestantes (témoins et recevant la diète faible en sodium) sont sacrifiées au jour 22 de gestation (sur 23). Les coeurs foetaux sont prélevés afin de caractériser les protéines dites « limitantes » in vitro des voies de la glycolyse et de la β-oxydation. Les expressions protéiques de GLUT1, GLUT4, HK1, HK2, CPT2, CPT1β, cytochrome c, PFK1, PKM1/2, mesurées par immunobuvardage de type Western, sont similaires entre les coeurs des foetus RCIU et témoins, mâles et femelles. L’expression protéique de CPT1α est diminuée dans les coeurs des femelles RCIU seulement. Il n’existe aucune différence significative entre les différents groupes quant à l’activité enzymatique de PKM1/2. Nos résultats dressent un profil métabolique général suggérant que le sexe du foetus peut avoir un effet sur la réponse cardiaque foetale à une atteinte du volume sanguin maternel causée par la diète restreinte en sodium. Ce profil métabolique semble démontrer une atteinte du catabolisme des lipides. Afin de bien caractériser cette réponse du mécanisme énergétique, l’activité enzymatique des autres enzymes principales de la glycolyse (HK1, HK2, PFK1), le flux intra-mitochondrial d’acyl CoA à travers les CPTs ainsi que la quantité totale d’acétyl CoA devront être quantifiés.A low sodium diet was given to pregnant rats during the last week of gestation. This diet diminished the maternal expansion of blood volume, the uterine arteries diameter, and placental weight, when compared to their controls. Together, these results suggest a lower placenta perfusion and a decreased output of nutrients to the fetus. The offspring of these pregnant rats were born with an intra-uterine growth retardation (IUGR). The fetal heart utilizes glucose through glycolysis as the major cardiac energy substrate. At birth, the principal source of energy switches to the oxidation of fatty acids, through β-oxydation. We hypothesized that within our IUGR model, the fetal heart could respond to a diminished nutritional intake due to the maternal input when a decreased cardiac energy metabolism was present. The pregnant rats of both groups (controls and on the low sodium diet) were sacrificed on day 22 of a 23 day gestation. The fetal hearts were then analyzed looking for signs of the limiting proteins glycolysis and β-oxidation. The GLUT1, GLUT4, HK1, HK2, CPT2, CPT1β, cytochrome c, PFK1, PKM1/2 proteins obtained through a Western immunoblot method were similar between the hearts of the IUGR and their control fetuses, whether they were male or female. The protein expression of CPT1α was lower only in female IUGR fetal hearts. There was no significant difference between the groups with respect to the enzymatic activity of PKM1/2. Our results suggest that the metabolic profile changes with regards to the fetus gender and could affect the fetal cardiac metabolism, due to a lower maternal blood flow caused by a sodium controlled diet, by diminishing its lipid metabolism and sparing glucose metabolism. To characterize the energy metabolism, the enzymatic activity of the other principal limiting enzymes glycolysis (HK1, HK2, PFK1), the intra-mitochondrial flux of acyl CoA through the CPTs and the total quantity of acetyl CoA must also be analyzed

On the Origin of Biomolecular Networks

Biomolecular networks have already found great utility in characterizing complex biological systems arising from pairwise interactions amongst biomolecules. Here, we explore the important and hitherto neglected role of information asymmetry in the genesis and evolution of such pairwise biomolecular interactions. Information asymmetry between sender and receiver genes is identified as a key feature distinguishing early biochemical reactions from abiotic chemistry, and a driver of network topology as biomolecular systems become more complex. In this context, we review how graph theoretical approaches can be applied not only for a better understanding of various proximate (mechanistic) relations, but also, ultimate (evolutionary) structures encoded in such networks from among all types of variations they induce. Among many possible variations, we emphasize particularly the essential role of gene duplication in terms of signaling game theory, whereby sender and receiver gene players accrue benefit from gene duplication, leading to a preferential attachment mode of network growth. The study of the resulting dynamics suggests many mathematical/computational problems, the majority of which are intractable yet yield to efficient approximation algorithms, when studied through an algebraic graph theoretic lens. We relegate for future work the role of other possible generalizations, additionally involving horizontal gene transfer, sexual recombination, endo-symbiosis, etc., which enrich the underlying graph theory even further