ABSTRACT
Acremonium chrysogenum is an ascomycete fungus isolated by Giuseppe Brotzu from sewage-contaminated marine waters. It is industrially used for the production of cephalosporins, a class of medically important β-lactams for the treatment of several bacterial infections. Due to this importance, the genes encoding the cephalosporin biosynthetic enzymes have received considerable attention. The cephalosporin biosynthetic genes are arranged in two clusters located in different chromosomes. The “early” cluster contains the genes pcbAB and pcbC, which encode the enzymes involved in the biosynthesis of the intermediate isopenicillin N (IPN), cefD1 and cefD2, which encode a two-protein system involved in the epimerization of IPN to penicillin N (PenN) and the membrane transporter encoding genes cefT, cefM and cefP. This cluster is located in chromosome VII, the largest chromosome resolved from the A. chrysogenum genome. A second cluster, named the “late” gene cluster located in chromosome I, encodes the two last steps of cephalosporin biosynthesis; cefEF and cefG. The enzymes encoded by these two genes catalyze the conversion of PenN to deacetylcephalosporin C (DAC) and fi nally, to cephalosporin C. Most of the enzymes encoded by these genes have been characterized from the biochemical point of view and three of them (the IPN synthase, the deacetoxycephalosporin C (DAOC) synthase/hydroxylase and the DAC acetyltransferase) have been crystallized. The organization of the cephalosporin genes in two clusters requires that expression of the genes in the two separate clusters is coordinated for optimal yield of cephalosporin. In strains in which there is not a good coordination, considerable amounts of the IPN or PenN intermediates (compounds having weak antibiotic activity) are secreted to the culture medium.
