The Biosynthesis of Penicillin and Cephalosporin C are Regulated by ROS at Transcriptional Level

In a recent work we showed that, besides lovastatin, ROS also accumulate during the production phase in Pencillium chrysogenum and in Acremonium chrysogenum, and that these ROS regulate the biosynthesis of penicillin and cephalosporin C. In the present study, we investigated the level at which this positive regulation is exerted. Internal ROS levels were manipulated, i.e., increased or decreased, in the production phase of the respective fermentations. Penicillin production decreased by 51.2% when internal ROS concentration was diminished by 50%, while a 62% production increase was observed when ROS were increased (62%). Similarly, Cephalosporin production decreased (35%) with antioxidants and increased (54.1%) with exogenous ROS. Expression analysis of the respective pcbAB genes, encoding the non-ribosomal peptide synthetase enzymes, was performed. Results showed down regulation of these genes in fermentations with lower ROS content, and upregulation in the cultures with higher ROS content, in both species. This showed that ROS regulation of penicillin in P. chrysogenum and of cephalosporin C in A. chrysogenum, is exerted at transcriptional level. In silico analysis of the pcbAB gene promoters in both species, suggested that this regulation could be mediated by stress-response transcription factors like Yap1, SrrA and/or MsnA, and/or by the Hap complex.