Effect of cycling dissolved oxygen concentrations on product formation in penicillin fermentations

Vardar, Filiz; Lilly, M. D.

doi:10.1007/bf00498464

Cited by 149 publications

(80 citation statements)

References 24 publications

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“…These changes could be correlated to the EDC function. These results were in broad agreement with those reported by König et al (1981), Vardar and Lilly (1982), Smith et al (1990), and Makagiansar et al (1993). The mean projected area also increased in the batch phase and remained relatively constant (dependent on agitation intensity) in the stationary phase.…”

Section: -432 Penicillium Chrysogenumsupporting

confidence: 93%

“…Second, it has not been possible to dissociate the influence of agitation from mass transfer effects. The dependence of product formation rates on impeller-generated fluid dynamic stresses has been observed for a wide variety of filamentous fungi (Ujcova et al, 1980;Vardar and Lilly, 1982;Smith et al, 1990;Braun and Vecht-Lifshitz, 1991;Märkl et al, 1991;Merchuk, 1991). There are also reports that mycelial fragmentation depends on the physiological state of the microorganisms (Smith et al, 1990;Paul et al, 1994).…”

Section: -4 Mycelial Fermentationsmentioning

confidence: 91%

“…A number of studies have implemented such strategies (Vardar and Lilly, 1982;Sokolov et al, 1983), and the reader is referred to these papers for further details. An easier setup to simulate dissolved oxygen gradients using a single well-mixed compartment would be to use timed pulsing of mixtures of nitrogen and oxygen (Oosterhuis, 1984;Sweere et al, 1988a,b;Namdev et al, 1991).…”

Section: Well-mixed Single-compartment Model (Str)mentioning

confidence: 98%

“…Many of the inhomogeneities encountered in production scale fermenters are cyclic in nature and can be approximated by forced sine-or square-wave functions. Such periodic fluctuations lead to every point on the sine or square wave describing a change in pressure, dissolved oxygen, or substrate concentration as a function of time (Vardar and Lilly, 1982). Therefore, each point represents a different region in a mechanically agitated vessel or a discrete element of fluid in circulation through the micro-and macromixed regions of the vessel.…”

Section: -27 Effects Of Fluctuating Environmental Conditions On MImentioning

confidence: 99%

See 3 more Smart Citations

Mixing in the Fermentation and Cell Culture Industries

Amanullah¹,

Buckland²,

Nienow

2003

Handbook of Industrial Mixing

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Section: -432 Penicillium Chrysogenumsupporting

confidence: 93%

Section: -4 Mycelial Fermentationsmentioning

confidence: 91%

Section: Well-mixed Single-compartment Model (Str)mentioning

confidence: 98%

Section: -27 Effects Of Fluctuating Environmental Conditions On MImentioning

confidence: 99%

See 2 more Smart Citations

Mixing in the Fermentation and Cell Culture Industries

Amanullah¹,

Buckland²,

Nienow

2003

Handbook of Industrial Mixing

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“…Most examples are at laboratory scale and few have truly separated the impact of dissolved oxygen from agitation. Vardar and Lilly (1982) showed the critical dissolved oxygen tension (C crit ) for penicillin production was 30% air saturation. Below this value, the speci®c production rate was signi®cantly reduced.…”

Section: Introductionmentioning

confidence: 99%

Pilot‐scale process sensitivity studies for the scaleup of a fungal fermentation for the production of pneumocandins

Pollard

Kirschner²,

Hernandez³

et al. 2002

Biotech & Bioengineering

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The filamentous fungus Glarea lozoyensis produces a novel, pharmaceutically important pneumocandin (B(0)) that is used to synthesize a lipopeptide which demonstrates cidal activity against clinically relevant pathogens. A range of unwanted pneumocandin analogs are also produced by the organism. To maintain the unwanted impurities to acceptable levels upon scaleup, a good understanding of the impact of chemical and physical environment on the cell physiology is required, which benefits downstream processing. Pilot-scale studies were performed to determine the impact of dissolved oxygen, temperature, pH, and carbon dioxide on the process. Experiments included multiple fermenters (up to seven) at 0.07 and 0.8 m(3) scale using single source medium sterilization and inoculum. Gas blending was used to separate effects of dissolved oxygen from agitation. The process was significantly influenced by dissolved oxygen level. The critical dissolved oxygen tension (C(crit)) for growth was below 2% air saturation. The C(crit) for production of pneumocandin B(0) was 20% air saturation, with a significant reduction of the specific production rate below this value. In contrast, low dissolved oxygen levels produced a substantial increase of pneumocandins B(1), B(5), and E(0), while high dissolved oxygen levels produced a disproportionate increase of D(5). This sensivity to dissolved oxygen was independent of agitation within a power range of 2-15 kW/m(3). Broth viscosity was impacted below 10% dissolved oxygen, suggesting an effect on morphology. The process was shown to be sensitive to temperature but relatively insensitive to pH and carbon dioxide (in the exhaust gas) within the ranges studied. This scaledown analysis explained phenomena seen at pilot scale and helped define operating boundary conditions for successful scale up to 19 m(3).

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Pathway kinetics and metabolic control analysis of a high-yielding strain ofPenicillium chrysogenum during fed batch cultivations

Pissara

Nielsen

Bazin

1996

Biotechnol. Bioeng.

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A kinetic model representing the pathway for the biosynthesis of penicillin by P. chrysogenum has been developed. The model is capable of describing the flux through the biosynthetic pathway, and model simulations correspond well with measurements of intermediates and end products. One feature of the present model structure is that it assumes the kinetics of the enzyme isopenicillin N synthetase (IPNS) to be first order with respect to the dissolved oxygen concentration in the range of 0.070 to 0.18 mM (25% to 70% saturation with air). Thus, it indicates the importance that molecular oxygen has on the rate of the reaction catalyzed by this enzyme, and consequently as an enhancer of the specific rate of penicillin production. Using the kinetic model, metabolic control analysis (MCA) of the pathway was performed. The determined flux control coefficients suggested that, during the production phase, the flux is controlled by IPNS as this enzyme becomes saturated with tripeptide δ‐(L‐α‐amino‐adipyl)‐L‐cysteinyl‐D‐valine (LLD‐ACV). In the simulations, oxygen was shown to be a bottleneck alleviator by stimulating the rate of IPNS which prevents the accumulation of LLD‐ACV. As a consequence of this stimulation, the rate‐controlling step was moved to another place in the pathway. © 1996 John Wiley & Sons, Inc.

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Effect of cycling dissolved oxygen concentrations on product formation in penicillin fermentations

Cited by 149 publications

References 24 publications

Mixing in the Fermentation and Cell Culture Industries

Mixing in the Fermentation and Cell Culture Industries

Pilot‐scale process sensitivity studies for the scaleup of a fungal fermentation for the production of pneumocandins

Pathway kinetics and metabolic control analysis of a high-yielding strain ofPenicillium chrysogenum during fed batch cultivations

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