MOLECULAR REGULATION OF BETA-LACTAM BIOSYNTHESIS IN FILAMENTOUS FUNGI

The most commonly used beta-lactam antibiotics for the therapy of infe ctious diseases are penicillin and cephalosporin. Penicillin is produc ed as an end product by some fungi, most notably by Aspergillus (Emeri cella) nidulans and Penicillium chrysogenum. Cephalosporins are synthe sized by both bacteria and fungi, e.g., by the fungus Acremonium chrys ogenum (Cephalosporium acremonium). The biosynthetic pathways leading to both secondary metabolites start from the same three amino acid pre cursors and have the first two enzymatic reactions in common. Penicill in biosynthesis is catalyzed by three enzymes encoded by acvA (pcbAB) ipnA (pcbC), and aatA (penDE). The genes are organized into a cluster. In A. chrysogenum, in addition to acvA and ipnA, a second cluster con tains the genes encoding enzymes that catalyze the reactions of the la ter steps of the the cephalosporin pathway (cefEF and cefG). Within th e last few years, several studies have indicated that the fungal beta- lactam biosynthesis genes are controlled by a complex regulatory netwo rk, e.g., by the ambient pH, carbon source, and amino acids. A compari son with the regulatory mechanisms (regulatory proteins and DNA elemen ts) involved in the regulation of genes of primary metabolism in lower eukaryotes is thus of great interest. This has already led to the elu cidation of new regulatory mechanisms. Furthermore, such investigation s have contributed to the elucidation of signals leading to the produc tion of beta-lactams and their physiological meaning for the producing fungi, and they can be expected to have a major impact on rational st rain improvement programs. The knowledge of biosynthesis genes has alr eady been used to produce new compounds.