Characterization of the metabolic shift between oxidative and fermentative growth in Saccharomyces cerevisiae by comparative 13C flux analysis

Frick, Oliver; Wittmann, Christoph

doi:10.1186/1475-2859-4-30

Cited by 170 publications

(94 citation statements)

References 50 publications

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“…As the dilution rate was increased to 0.30 h -1 there was, moreover, a sharp increase in extracellular acetate concentration, also typical for the shift to partly fermentative growth in S. cerevisiae . This point of respiro-fermentative onset correlates with previous found values for S. cerevisiae [29,30], indicating that the EFE does not impose any drastic metabolic burden on the cell.…”

Section: Resultssupporting

confidence: 88%

Identification of factors for improved ethylene production via the ethylene forming enzyme in chemostat cultures of Saccharomyces cerevisiae

et al. 2013

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BackgroundBiotechnological production of the traditional petrochemical ethylene is presently being explored using yeasts as well as bacteria. In this study we quantify the specific ethylene production levels at different conditions in continuous (chemostat) cultivation of Saccharomyces cerevisae expressing the ethylene forming enzyme (EFE) from Pseudomonas syringae.ResultsOur study shows that oxygen availability is an important factor for the ethylene formation. Maintaining a high percentage dissolved oxygen in the cultivation was found to be necessary to achieve maximal ethylene productivity. Even at oxygen levels high enough to sustain respiratory metabolism the ethylene formation was restricted. Oxygen was also important for sustaining a high respiratory rate and to re-oxidize the surplus of NADH that accompanies ethylene formation. By employing three different nitrogen sources we further found that the nitrogen source available can both improve and impair the ethylene productivity. Contrary to findings in batch cultures, using glutamate did not give a significant increase in specific ethylene production levels compared to the reference condition with ammonia, whereas a combination of glutamate and arginine resulted in a strongly diminished specific ethylene production. Furthermore, from cultivations at different dilution rates the ethylene formation was found to be coupled to growth rate.ConclusionTo optimize the ethylene productivity in S. cerevisiae expressing a bacterial ethylene forming enzyme, controlling the oxygen availability and growth rate as well as employing an ideal nitrogen source is of importance. The effects of these factors as studied here provide a basis for an optimized process for ethylene production in S. cerevisiae.

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Section: Resultssupporting

confidence: 88%

Identification of factors for improved ethylene production via the ethylene forming enzyme in chemostat cultures of Saccharomyces cerevisiae

et al. 2013

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“…Isotopic labeling was not used in this study to probe internal fluxes due to limitations related to cost and time. Nevertheless, our inferred fluxes agree well with those that have previously been found using 13C-based metabolic flux analysis (MFA) of carbon-limited yeast cultures (19, 20). The generally good agreement can be understood in terms of the sufficiency of boundary fluxes for constraining many fluxes of interest.…”

Section: Methodssupporting

confidence: 90%

Systems-level analysis of mechanisms regulating yeast metabolic flux

Hackett

Zanotelli

et al. 2016

Science

266

300

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Cellular metabolic fluxes are determined by enzyme activities and metabolite abundances. Biochemical approaches reveal the impact of specific substrates or regulators on enzyme kinetics, but do not capture the extent to which metabolite and enzyme concentrations vary across physiological states, and therefore how cellular reactions are regulated. We measured enzyme and metabolite concentrations and metabolic fluxes across 25 steady-state yeast cultures. We then assessed the extent to which flux can be explained by a Michaelis-Menten relationship between enzyme, substrate, product, and potential regulator concentrations. This revealed three new instances of cross-pathway regulation, which we biochemically verified. These included inhibition of pyruvate kinase by citrate, which accumulated and thereby curtailed glycolytic outflow in nitrogen-limited yeast. Overall, substrate concentrations were the strongest driver of the net rates of cellular metabolic reactions, with metabolite concentrations collectively having more than double the physiological impact of enzymes.

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“…For instance, under aerobic growth conditions fast growing E. coli and S. cerevisiae cells also exhibit aerobic glycolysis, resulting in the excretion of the metabolic byproducts, acetate and ethanol, respectively. More importantly, both for E. coli and for S. cerevisiae a shift toward aerobic glycolysis follows a switch from limited to rich nutrient conditions [28,29], and for E. coli the maximum growth rates in different carbon sources and the mode of utilization of mixed carbon sources are in agreement with those allowed by the limited solvent capacity of the cell's cytoplasm [29,30]. Taken together with our current finding for mammalian cells, these results suggest that the appearance of aerobic glycolysis provides an energetically favorable catabolic state for all rapidly proliferating cells due to the inherent physicochemical constraint of molecular crowding on cell metabolism.…”

Section: Discussionmentioning

confidence: 99%

Catabolic efficiency of aerobic glycolysis: The Warburg effect revisited

Vazquez¹,

et al. 2010

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BackgroundCancer cells simultaneously exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen, a phenomenon known as the Warburg effect. The maintenance of this mixed metabolic phenotype is seemingly counterintuitive given that aerobic glycolysis is far less efficient in terms of ATP yield per moles of glucose than mitochondrial respiration.ResultsHere, we resolve this apparent contradiction by expanding the notion of metabolic efficiency. We study a reduced flux balance model of ATP production that is constrained by the glucose uptake capacity and by the solvent capacity of the cell's cytoplasm, the latter quantifying the maximum amount of macromolecules that can occupy the intracellular space. At low glucose uptake rates we find that mitochondrial respiration is indeed the most efficient pathway for ATP generation. Above a threshold glucose uptake rate, however, a gradual activation of aerobic glycolysis and slight decrease of mitochondrial respiration results in the highest rate of ATP production.ConclusionsOur analyses indicate that the Warburg effect is a favorable catabolic state for all rapidly proliferating mammalian cells with high glucose uptake capacity. It arises because while aerobic glycolysis is less efficient than mitochondrial respiration in terms of ATP yield per glucose uptake, it is more efficient in terms of the required solvent capacity. These results may have direct relevance to chemotherapeutic strategies attempting to target cancer metabolism.

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Characterization of the metabolic shift between oxidative and fermentative growth in Saccharomyces cerevisiae by comparative 13C flux analysis

Cited by 170 publications

References 50 publications

Identification of factors for improved ethylene production via the ethylene forming enzyme in chemostat cultures of Saccharomyces cerevisiae

Identification of factors for improved ethylene production via the ethylene forming enzyme in chemostat cultures of Saccharomyces cerevisiae

Systems-level analysis of mechanisms regulating yeast metabolic flux

Catabolic efficiency of aerobic glycolysis: The Warburg effect revisited

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