Regulation of penicillin biosynthesis in filamentous fungi.

The beta-lactam antibiotic penicillin is one of the mainly used antibiotics for the therapy of infectious diseases. It is produced as end product by some filamentous fungi only, most notably by Aspergillus (Emericella) nidulans and Penicillium chrysogenum. The penicillin biosynthesis is catalysed by three enzymes which are encoded by the following three genes: acvA (pcbAB), ipnA (pcbC) and aatA (penDE). The genes are organised into a gene cluster. Although the production of secondary metabolites as penicillin is not essential for the direct survival of the producing organisms, several studies indicated that the penicillin biosynthesis genes are controlled by a complex regulatory network, e.g. by the ambient pH, carbon source, amino acids, nitrogen etc. A comparison with the regulatory mechanisms (regulatory proteins and DNA elements) involved in the regulation of genes of primary metabolism in lower eukaryotes is thus of great interest. This has already led to the elucidation of new regulatory mechanisms. Positively acting regulators have been identified such as the pH dependent transcriptional regulator PACC, the CCAAT-binding complex AnCF and seem also to be represented by recessive trans-acting mutations of A. nidulans (prgA1, prgB1, npeE1) and R chrysogenum (carried by mutants Npe2 and Npe3). In addition, repressors like AnBH1 and VeA are involved in the regulation. Furthermore, such investigations have contributed to the elucidation of signals leading to the production of penicillin and can be expected to have a major impact on rational strain improvement programs.