Improvement of growth yield of yeast on glucose to the maximum by using an additional energy source

Babel, Wolfgang; Müller, Roland; Markuske, Klaus D.

doi:10.1007/bf00409845

Arch. Microbiol.

1983

DOI: 10.1007/bf00409845

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Improvement of growth yield of yeast on glucose to the maximum by using an additional energy source

Wolfgang Babel¹,

Roland Müller²,

Klaus D. Markuske³

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1985

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Cited by 51 publications

(27 citation statements)

References 21 publications

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“…This response to an auxiliary substrate is not, at first glance, surprising: increased growth yields attributable to a second catabolic substrate have been previously reported (2,13). In these reports the maximum specific growth rates remained unaltered, being fixed by carbon flux limitations.…”

supporting

confidence: 53%

Electrogenic malate uptake and improved growth energetics of the malolactic bacterium Leuconostoc oenos grown on glucose-malate mixtures

et al. 1992

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Growth of the malolactic bacterium Leuconostoc oenos was improved with respect to both the specific growth rate and the biomass yield during the fermentation ofglucose-malate mixtures as compared with those in media lacking malate. Such a finding indicates that the malolactic reaction contributed to the energy budget of the bacterium, suggesting that growth is energy limited in the absence of malate. An energetic yield (YATP) of 9.5 g of biomass mol ATP'1 was found during growth on glucose with an ATP production by substrate-level phosphorylation of 1.2 mol of ATP. mol of glucose-'. During the period of mixed-substrate catabolism, an apparent YATP of 17.7 was observed, indicating a mixotrophy-associated ATP production of 2.2 mol of ATP-mol of glucose 1, or more correctly an energy gain of 0.28 mol of ATP-mol of malate-1, representing proton translocation flux from the cytoplasm to the exterior of 0.56 or 0.84 H+ mol of malate'1 (depending on the H+/ATP stoichiometry). The growth-stimulating effect of malate was attributed to chemiosmotic transport mechanisms rather than proton consumption by the malolactic enzyme. Lactate efflux was by electroneutral lactatef/H+ symport having a constant stoichiometry, while malate uptake was predominantly by a malate-/H+ symport, though a low-affinity malate-uniport was also implicated. The measured electrical component (A*) of the proton motive force was altered, passing from -30 to -60 mV because of this translocation of dissociated organic acids when malolactic fermentation occurred.Certain species of lactic acid bacteria (belonging to the genera Lactobacillus, Pediococcus, and Leuconostoc) possess the capacity to convert malate to lactate via a direct decarboxylation reaction referred to as malolactic fermentation. This fermentation is of use in the enological industry since it enables the removal of excess acidity, enhances organoleptic properties, and increases the bacteriological stability of wine (7,33).Those bacteria able to metabolize malate via malolactic fermentation show improved growth characteristics when presented with glucose-malate mixtures as compared with the growth characteristics during fermentation of glucose alone. This response to an auxiliary substrate is not, at first glance, surprising: increased growth yields attributable to a second catabolic substrate have been previously reported (2, 13). In these reports the maximum specific growth rates remained unaltered, being fixed by carbon flux limitations. More recently, improved growth yields and specific growth rates have been achieved with substrate mixtures which overcome both carbon flux and energetic limitations simultaneously (15). In the case of the malolactic bacteria, the situation is somewhat different in that the malate cannot contribute directly to the anabolic carbon flux and, furthermore, there is no energy conservation at the enzyme level (either directly by substrate-level phosphorylation [SLP] or indirectly via reducing equivalent generation). The reaction involved in the decarboxylatio...

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supporting

confidence: 53%

Electrogenic malate uptake and improved growth energetics of the malolactic bacterium Leuconostoc oenos grown on glucose-malate mixtures

et al. 1992

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“…These results are likely to be a combination of effects from alleviating the feedback inhibition of the TCA cycle by mitochondrial NADH and increasing respiratory capacity due to improved efficiency of oxidative phosphorylation, as quantified by the P/O ratio (15). There are no reports that describe the effect of increasing NADH in S. cerevisiae, although formate has been used previously as a source of additional reducing power in S. cerevisiae (2,4,11,23,24,27). Formate (HCOO Ϫ ) is efficiently oxidized to CO 2 by NAD ϩ -dependent formate dehydrogenase (27) and, therefore, cannot be used as a carbon source for biomass synthesis.…”

mentioning

confidence: 99%

Metabolic Impact of Increased NADH Availability in Saccharomyces cerevisiae

Hou

Scalcinati

Oldiges

et al. 2010

Appl Environ Microbiol

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Engineering the level of metabolic cofactors to manipulate metabolic flux is emerging as an attractive strategy for bioprocess applications. We present the metabolic consequences of increasing NADH in the cytosol and the mitochondria of Saccharomyces cerevisiae. In a strain that was disabled in formate metabolism, we either overexpressed the native NAD ؉ -dependent formate dehydrogenase in the cytosol or directed it into the mitochondria by fusing it with the mitochondrial signal sequence encoded by the CYB2 gene. Upon exposure to formate, the mutant strains readily consumed formate and induced fermentative metabolism even under conditions of glucose derepression. Cytosolic overexpression of formate dehydrogenase resulted in the production of glycerol, while when this enzyme was directed into the mitochondria, we observed glycerol and ethanol production. Clearly, these results point toward different patterns of compartmental regulation of redox homeostasis. When pulsed with formate, S. cerevisiae cells growing in a steady state on glucose immediately consumed formate. However, formate consumption ceased after 20 min. Our analysis revealed that metabolites at key branch points of metabolic pathways were affected the most by the genetic perturbations and that the intracellular concentrations of sugar phosphates were specifically affected by time. In conclusion, the results have implications for the design of metabolic networks in yeast for industrial applications.The traditional use of baker's yeast, Saccharomyces cerevisiae, for ethanol production has resulted in the accumulation of substantial information about its genetics, metabolism, and process development. Consequently, the collection of compounds that are produced using S. cerevisiae has expanded to include organic acids and even secondary metabolites (1,25,28). Unlike ethanol, many of these products are not redox neutral relative to commonly used substrates such as glucose. Therefore, in addition to stoichiometry, redox constraints play an important role in the formation of the products. Additional reducing power has to be supplied to produce compounds whose degree of reduction is higher than that of the substrate. On the other hand, producing compounds with a degree of reduction lower than that of the substrate will force the synthesis of other compounds with higher degrees of reduction to compensate for excess reducing power generated from substrate oxidation. These constraints may decrease the product yield substantially.The catabolic currency that balances the degree of reduction between the substrate and the products is usually NADH. In S. cerevisiae, NADH is produced in the cytosol by mainly glyceraldehyde-3-phosphate dehydrogenase and other assimilatory reaction enzymes (35). In the mitochondria, NADH is formed in the tricarboxylic acid (TCA) cycle and the reaction of the pyruvate dehydrogenase complex. Cytosolic NADH is oxidized by the glycerol-3-phosphate shuttle or the external cytosolic NADH dehydrogenases, which are part of the electron transp...

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“…Since part of the glucose has to be used for the generation of ATP equivalents in dissimilation, it can be called an energy-deficient substrate (4). Due to this intrinsic free energy deficiency, experimentally obtained biomass yields on glucose are generally lower than the maximum biomass yield that could theoretically be reached when assimilatory reactions are fully optimized (5,9).…”

mentioning

confidence: 99%

Formate as an Auxiliary Substrate for Glucose-Limited Cultivation of Penicillium chrysogenum : Impact on Penicillin G Production and Biomass Yield

Harris

Krogt

Gulik

et al. 2007

Appl Environ Microbiol

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Production of ␤-lactams by the filamentous fungus Penicillium chrysogenum requires a substantial input of ATP. During glucose-limited growth, this ATP is derived from glucose dissimilation, which reduces the product yield on glucose. The present study has investigated whether penicillin G yields on glucose can be enhanced by cofeeding of an auxiliary substrate that acts as an energy source but not as a carbon substrate. As a model system, a high-producing industrial strain of P. chrysogenum was grown in chemostat cultures on mixed substrates containing different molar ratios of formate and glucose. Up to a formate-to-glucose ratio of 4.5 mol ⅐ mol ؊1 , an increasing rate of formate oxidation via a cytosolic NAD ؉ -dependent formate dehydrogenase increasingly replaced the dissimilatory flow of glucose. This resulted in increased biomass yields on glucose. Since at these formate-to-glucose ratios the specific penicillin G production rate remained constant, the volumetric productivity increased. Metabolic modeling studies indicated that formate transport in P. chrysogenum does not require an input of free energy. At formate-to-glucose ratios above 4.5 mol ⅐ mol ؊1 , the residual formate concentrations in the cultures increased, probably due to kinetic constraints in the formate-oxidizing system. The accumulation of formate coincided with a loss of the coupling between formate oxidation and the production of biomass and penicillin G. These results demonstrate that, in principle, mixed-substrate feeding can be used to increase the yield on a carbon source of assimilatory products such as ␤-lactams.The filamentous fungus Penicillium chrysogenum is applied on a large scale (Ͼ60,000 tons year Ϫ1 ) (8, 36) for the industrial production of ␤-lactam antibiotics, such as penicillin G and penicillin V, and for the production of the cephalosporin precursor adipoyl-7-ADCA. ␤-Lactam antibiotics are formed in a multistep process in which the first two steps are common for penicillins and cephalosporins. The three amino acids cysteine, valine, and ␣-aminoadipic acid, derived from central metabolism, are condensed to form the tripeptide ACV (␣-aminoadipyl-cysteinyl-valine). The next step is a ring closure that leads to the characteristic penam structure of isopenicillin N, the branch point intermediate at which penicillin biosynthesis diverges from cephalosporin biosynthesis. Penicillin G is formed from isopenicillin N by exchanging its ␣-aminoadipic acid side chain for phenylacetic acid, using phenylacetyl-coenzyme A as a side chain donor.Overproduction of secondary metabolites can have a large impact on central metabolism if it requires significant amounts of carbon precursors, reducing equivalents (NADH and NADPH), and free energy equivalents (ATP). Previous studies on penicillin G production in a high-producing industrial strain of P. chrysogenum have shown that constraints in central metabolism may reside in the supply and regeneration of the cofactor NADPH rather than in the supply of the carbon precursors, ␣-aminoadipic aci...

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Improvement of growth yield of yeast on glucose to the maximum by using an additional energy source

Cited by 51 publications

References 21 publications

Electrogenic malate uptake and improved growth energetics of the malolactic bacterium Leuconostoc oenos grown on glucose-malate mixtures

Electrogenic malate uptake and improved growth energetics of the malolactic bacterium Leuconostoc oenos grown on glucose-malate mixtures

Metabolic Impact of Increased NADH Availability in Saccharomyces cerevisiae

Formate as an Auxiliary Substrate for Glucose-Limited Cultivation of Penicillium chrysogenum : Impact on Penicillin G Production and Biomass Yield

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