title: Scale-down of penicillin production in Penicillium chrysogenum.
abstract: In large-scale production reactors the combination of high broth viscosity and large broth volume leads to insufficient liquid-phase mixing, resulting in gradients in, for example, the concentrations of substrate and oxygen. This often leads to differences in productivity of the full-scale process compared with laboratory scale. In this scale-down study of penicillin production, the influence of substrate gradients on process performance and cell physiology was investigated by imposing an intermittent feeding regime on a laboratory-scale culture of a high yielding strain of Penicillium chrysogenum. It was found that penicillin production was reduced by a factor of two in the intermittently fed cultures relative to constant feed cultivations fed with the same amount of glucose per hour, while the biomass yield was the same. Measurement of the levels of the intermediates of the penicillin biosynthesis pathway, along with the enzyme levels, suggested that the reduction of the flux through the penicillin pathway is mainly the result of a lower influx into the pathway, possibly due to inhibitory levels of adenosine monophosphate and pyrophosphate and lower activating levels of adenosine triphosphate during the zero-substrate phase of each cycle of intermittent feeding.
authors.affiliation: Bioprocess Technology, Department of Biotechnology, Delft University of Technology, Delft, The Netherlands.
authors.forename: Lodewijk P
authors.initials: LP
authors.lastname: de Jonge
authors.forename: Nicolaas A A
authors.initials: NA
authors.lastname: Buijs
authors.forename: Angela
authors.initials: A
authors.lastname: ten Pierick
authors.forename: Amit
authors.initials: A
authors.lastname: Deshmukh
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.forename: Jan A K W
authors.initials: JA
authors.lastname: Kiel
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Heijnen
authors.forename: Walter M
authors.initials: WM
authors.lastname: van Gulik
mesh_terms: D057486:Carbon Cycle; D003066:Coenzyme A Ligases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007218:Industrial Microbiology; D053858:Metabolic Networks and Pathways; D010088:Oxidoreductases / Q000378:metabolism; D010406:Penicillins / Q000096:biosynthesis*; D010408:Penicillium chrysogenum / Q000737:chemistry / Q000378:metabolism*; D010453:Peptide Synthases / Q000378:metabolism
chemical_list: D010406:Penicillins; D010088:Oxidoreductases; C038370:isopenicillin N synthetase; D003066:Coenzyme A Ligases; D010453:Peptide Synthases; C095368:alpha-aminoadipyl-cysteinyl-valine synthetase; D005947:Glucose