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Applied and Environmental Microbiology, August 2007, p. 5020-5025, Vol. 73, No. 15
0099-2240/07/$08.00+0     doi:10.1128/AEM.00093-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Diana M. Harris, Zita A. van der Krogt, Walter M. van Gulik, Johannes P. van Dijken, and Jack T. Pronk*

Department of Biotechnology, Delft University of Technology, Julianalaan 67, 2628 BC Delft, The Netherlands

Received 15 January 2007/ Accepted 23 May 2007

Production of ß-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·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·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 ß-lactams.

* Corresponding author. Mailing address: Delft University of Technology, Department of Biotechnology, Julianalaan 67, 2628 BC Delft, The Netherlands. Phone: 31 152783214. Fax: 31 152782355. E-mail: j.t.pronk{at}tudelft.nl

{triangledown} Published ahead of print on 1 June 2007.

Applied and Environmental Microbiology, August 2007, p. 5020-5025, Vol. 73, No. 15
0099-2240/07/$08.00+0     doi:10.1128/AEM.00093-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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