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NADPH-dependent glutamate dehydrogenase in Penicillium chrysogenum is involved in regulation of β-lactam production

¹ Center for Microbial Biotechnology, Technical University of Denmark, Building 223, DK-2800 Lyngby, Denmark
² DSM-Anti-Infectives, Industrial Pharmaceutical Products Division, Wateringsweg 1, PO Box 1, NL-2600 MA Delft, Denmark

Correspondence
Jens Nielsen
jn{at}biocentrum.dtu.dk

The interactions between the ammonium assimilatory pathways and β-lactam production were investigated by disruption of the NADPH-dependent glutamate dehydrogenase gene (gdhA) in two industrial β-lactam-producing strains of Penicillium chrysogenum. The strains used were an adipoyl-7-ADCA- and a penicillin-producing strain. The gdhA gene disruption caused a decrease in maximum specific growth rate of 26 % and 35 % for the adipoyl-7-ADCA-producing strain and the penicillin-producing strain, respectively, compared to the corresponding reference strains. Interestingly, no β-lactam production was detected in either of the gdhA strains. Supplementation with glutamate restored growth but no β-lactam production was detected for the constructed strains. Cultures with high ammonium concentrations (repressing conditions) and with proline as nitrogen source (de-repressed conditions) showed continued β-lactam production for the reference strains whereas the gdhA strains remained non-productive under all conditions. By overexpressing the NAD-dependent glutamate dehydrogenase, the specific growth rate could be restored, but still no β-lactam production was detected. The results indicate that the NADPH-dependent glutamate dehydrogenase may be directly or indirectly involved in the regulation of β-lactam production in industrial strains of P. chrysogenum.