Cephalosporins biosynthetic genes

Y Aharonowitz, G Cohen, JF Martin. Penicillin and cephalosporin biosynthetic genes structure, organization, regulation and evolution. Annu Rev Microbiol 46 461-495, 1992. 

Figure 4.30 Genetic organization of the penicillm and cephalosporin biosynthetic gene clusters from the fungi Aspergillus nidulans, Penicillum chrysogenum, and Acremonium chrysogenum and from the bacteria Streptomyces clavuligerus and Lysobacter lactamgenus.

III. MOLECULAR ARCHITECTURE AND EVOLUTION OF PENICILLIN/CEPHALOSPORIN BIOSYNTHETIC GENES... 

Classical genetic mapping and molecular cloning studies have revealed that antibiotic biosynthesis and resistance genes are invariably clustered on the chromosomes of Strepio-myces and other actinomycetes (92.93). In keeping with this general rule, the penicillin/cephalosporin biosynthetic genes from all bacterial >ecies studied to date have... 

Recent developments by academic and industrial geneticists may well prove to have transformed this situation. Tremendous progress has been made since the mid-1980s both in the isolation and manipulation ofthe biosynthetic genes in this pathway and in the related routes to the cephalosporins (via the cephalosporin C-producing... 

WK Yeh, SW Queener. Potential industrial use of cephalosporin biosynthetic enzymes and genes. An overview. Ann NY Acad Sci 613 128-141, 1990. 

J Velasco, S Gutierrez, FJ Fernandez, AT Marcos, C Arenos, JF Martin. Exogenous methionine increases levels of mRNAs transcribed from pcbAB, pcbC, and ce/EF genes, encoding enzymes of the cephalosporin biosynthetic pathway, in Acremonium chrysogenum. J Bacteriol 176 985-991, 1994. 

Besides resistance genes, antibiotic biosynthetic gene clusters may also contain genes encoding transport/export proteins that ensure proper secretion of the antibiotic molecule (91). In N. tactamdurans, a gene, cmcT, has been identified in the penicillin/cephalosporin gene cluster that encodes a potential transmcmbranc protein possibly involved in export of the antibiotics (87). 

Figure 1 Biosynthetic pathway for cephalosporin C in C. acremonium, penicillin G in P. chrysogenum, and cephamycin C in S. clavuligerus. Gene designations are shown to the left of the arrows and enzyme designations are shown to the right.

The manufacture of several semisynthetic oral cephalosporin antibiotics involves the chemical ring expansion of penicillin V to 7-aminodeacetoxycephalosporanic acid (7-ADCA Fig. 2 [68]). This is a costly and potentially environmentally damaging process [69], Cloning of the C. acremonium cefEF gene (DAOCS/ DACS [47]) and the S. clavuligerus cefD (IPNE) and cefE gene (DAOCS [43]) opened the possibility for biosynthetic/enzymatic processes for production of 7-ADCA. 

A close relationship between eporulation and secondary biosynthesis by Streptomyces kanamyceticus (14) and in Streptomyces bikiniensis was described (l5). Non-sporu-lating variants were obtained with acriflavine treatment which lost the ability to produce the antibiotics. If it is assumed that the structural genes of the biosynthetic pathway are localized in chromosome, the deletion of ex-trachromosomal DNA may cause a loss of the ability to produce an endogenous inducer. Induction of the enzymes governing the formation of secondary metabolites would thus be closely associated with the expression of other traits, particularly sporulation. This fact was observed by Drew et al. (16) induction of cephalosporin C formation in Cephalosporium acremonium by methionine was ac-companied by arthrospore formation. 

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