Genes directly involved in the biosynthesis of beta-lactam antibiotics

Several genes encoding enzymatic activities involved in penicillin and cephalosporin biosynthesis have been identified. The first two steps in the biosynthesis of both antibiotics are common in penicillin, cephalosporin and cephamycin producers: condensation of the three precursor amino acids to form the tripeptide delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine, and oxidative cyclization of the tripeptide to form isopenicillin N. The genes involved in the two steps are pcbAB and pcbC respectively. The conversion of isopenicillin N to penicillin G is carried out by the enzyme isopenicillin N:6-APA acyltransferase encoded by the gene penDE. The biosynthesis of cephalosporin diverges from that of penicillin G at the isopenicillin N level. The isopenicillin N is first isomerized to penicillin N by an epimerase that is encoded by the gene cefD. The penicillin N is converted in deacetoxycephalosporin C by an expansion of the five-membered thiazolidine ring to the six-membered dihydrothiazine ring. The deacetoxycephalosporin C is finally converted into cephalosporin C by a hydroxylation and O-acetylation. The enzymes which catalyze these last three steps are encoded by the genes cefE, cefF and cefG. The penicillin, cephalosporin and cephamycin biosynthetic genes are organized in clusters (and subclusters) of genes.